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Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity
Abstract
Fifteen Amaryllidaceae alkaloids (1–15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are reported here for the first time. In their structure are combined two basic structural types of Amaryllidaceae alkaloids (galanthamine- and galanthindole-structural types), which represent a new structural type of these compounds. Alkaloids isolated in sufficient amounts were evaluated for their human erythrocytic acetylcholinesterase, and human serum butyrylcholinesterase (HuBuChE) inhibition activity using Ellman’s method. Z-Gly-Pro-p-nitroanilide was used as substrate in the prolyl oligopeptidase (POP) assay. Untested alkaloids were also screened for their cytotoxic activity against a small panel of human cancer cells, which spanned cell lines from different tissue types. In parallel, MRC-5 human fibroblasts were employed to determine overall toxicity against noncancerous cells. Some compounds were evaluated for their antiprotozoal activity. The newly isolated alkaloid narcipavline (5) showed interesting HuBuChE inhibition activity (IC50 = 24.4 ± 1.2 µM), and norlycoramine (11) demonstrated promising POP inhibition (IC50 = 0.21 ± 0.01 mM).
... Besides the economic value as ornamentals, the Narcissus plants possess notable application in traditional and western medicines as it contains more than hundreds of biologically active secondary metabolites called Amaryllidaceae alkaloids 3,9 . Among them, galanthamine and lycorine are the two best studied alkaloids and only galanthamine is produced on a commercial scale for the pharmaceutical industry 6,10 . ...
... Galanthamine is used as an acetylcholinesterase (AChE) inhibitor by increasing the concentration of acetylcholine at sites of neurotransmission and widely used in the treatment of early to mid-stage Alzheimer's disease 13 . Recently, galanthamine, homolycorine, haemanthamine, and lycoramine were reported for human serum butyrylcholinesterase (HuBuChE), human erythrocytic acetylcholinesterase (HuAChE) and prolyl oligopeptidase (POP) inhibitory activities 9 . Lycorine is a powerful inhibitor of ascorbic acid biosynthesis, cell growth, division, and organogenesis, which has been demonstrated to have antitumor and antiviral activities 14 . ...
... Hanks and Bastida et al., have previously reported similar mass fragments of homolycorine 7,11 . Crinamine (MW 301), detected in Carlton dormant bulb and basal plate was observed as the most abundant alkaloids along with lycorine and lycorenine in Narcissus bulb 35 which showed anti-tumour and moderate antimalarial activity 9,11,36 . A similar GC-MS fragmentation pattern as observed for crinamine in this study (Fig. 6d) was also reported for a similar compound, crinamine acetate (MW 343) isolated from an Amaryllidaceae species Crinum jagus L. 37 . ...
... Traub, Phaedranassa dubia (Kunth) J.F.Macbr. and Narcissus poeticus L. where it was inactive against P. falciparum, exhibited an IC 50 N 5 μg/mL against the K1 strain and shown to be weakly active against P. berghei (IC 50 N 30 μg/mL) (Herrera et al., 2001;Osorio et al., 2010;Safratova et al., 2018). Plasmodium berghei, P. chabaudi, P. vinckei and P. yoelii are the four Plasmodium species known to cause malaria in African murine rodents (Safratova et al., 2018). ...
... and Narcissus poeticus L. where it was inactive against P. falciparum, exhibited an IC 50 N 5 μg/mL against the K1 strain and shown to be weakly active against P. berghei (IC 50 N 30 μg/mL) (Herrera et al., 2001;Osorio et al., 2010;Safratova et al., 2018). Plasmodium berghei, P. chabaudi, P. vinckei and P. yoelii are the four Plasmodium species known to cause malaria in African murine rodents (Safratova et al., 2018). Sanguinine (11) alone has been reported in P. dubia whilst it together with its acyl analog 3-O-acetylsanguinine (12) were found in Crinum kirkii Baker and shown to be unresposive to both the chloroquine-resistant K1 and sensitive NF54 strains of P. falciparum (Machocho et al., 2004;Osorio et al., 2010). ...
... Salisb. and N. poeticus and shown to be inactive against both drug-sensitive (W-2) and drugresistant (D-6) strains of P. falciparum (Lin et al., 1995), with weak activity (IC 50 N 30 μg/mL) being seen against P. berghei (Safratova et al., 2018). The N-demethyl derivative epinorgalanthamine (14) which also happens to be epimerized at C-3 was isolated from an ethanolic whole plant extract of P. dubia, but subsequent screening against strain K1 failed to establish significant antiplasmodial activity for the compound (IC 50 N 5 μg/mL) (Osorio et al., 2010). ...
Malaria is responsible for majority of the morbidity and mortality statistics reflected by tropical diseases. Whilst effectively managed in most parts of the globe, it remains a scourge on the African continent where most cases of the disease are diagnosed annually. Plants have played a leading role as a source of malarial drugs which continue to dominate the clinical landscape today. Most if not all of these discoveries have as their basis evidence which can be traced back to traditional medicine. There is likewise precedence for the use of Amaryllidaceae plants in traditional medicinal approaches towards malaria. The chief phytochemical principles of the Amaryllidaceae are its isoquinoline alkaloids which are responsible for its diverse biological properties. These alkaloids may be divided into major and minor groups based on their distinguishing structural features as well as their natural abundance and distribution in the family. Whilst much has been written about the biological and chemical properties of the major alkaloid groups of the Amaryllidaceae, relatively little is known or understood about its minor alkaloid groups. This review focuses on the antiplasmodial activities described in the literature for the minor alkaloid group members of the Amaryllidaceae against various strains of the malarial pathogen Plasmodium falciparum. Three database platforms (Google Scholar, SciFinder and Scopus) were utilized for the literature search. Articles were accessed from journals licensed to the University of KwaZulu-Natal, or directly via the respective corresponding authors. Also considered are structural elements of these alkaloids which may be used to explain such activities as well as to provide a foundation in attempts to modulate activities. In addition, evidence is provided on the molecular basis to these effects which could guide efforts in drug discovery.
... Other heterodimeric alkaloids with a galanthamine-type moiety have been described in the past, namely pallidiflorine, narcipavline, narcikachnine, and narcimatuline [47][48][49]. The last three alkaloids were also isolated as a mixture of diastereomers by our research group, but there was no proposal for atropisomerism being the reason for isomerism at that time. ...
... Pink Parasol and N. pseudonarcissus cv. Dutch Master [narcipavline, narcikachnine, and narcimatuline ( Fig. 4)], the new alkaloid, narcieliine (3), displayed the most promising biological profile [47,48]. Narcipavline and narcimatuline displayed only weak hAChE inhibition potency (IC 50 > 200 µM for both compounds), and narcikachnine was not studied due to its isolation in low quantity. ...
... The remaining isolated alkaloids have already been studied for their biological profile within our previous studies on Amaryllidaceae plants, and are reported in the following literature [38,[46][47][48]54,55]. ...
Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.
... The latter examples demand further investigation on biogenetic origin and are not yet included on any particular type of AA. Some types of AA, such as plicamine and secoplicamine, are extracted in trace amounts exclusively from specific Amaryllidaceae species, such as Zephyranthes, but are classified in type X as they are rare, dinitrogenous members of AA, with a distinct biosynthetic linage [28][29][30][31]. Mesembrine alkaloids (also known as sceletium) have a distinct biosynthetic pathway, without norbelladine as key intermediate, they are usually extracted from Aizoaceae, but can be collected l-phenylalanine is converted to trans-cinnamic acid by the phenylalanine ammonia-lyase (PAL) ( Figure 2). ...
... Several of these novel AAs belong to known structural types, while others harbor new structures. The 91 AAs were classified in this manuscript as I) norbelladine-type (1-6), II) cherylline-type (7,8), III) galantamine-type (9-16), IV) lycorine-type (17)(18)(19)(20)(21)(22)(23)(24)(25), V) homolycorine-type (26)(27)(28)(29)(30), VI) crinine-type (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50), VII) narciclasine-type (51), VIII) pretazettine-type (52)(53)(54), IX) montanine-type (55), and X) other types including AAs related to plicamine (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67), seco-plicamine (68)(69)(70), cripowellin (71)(72)(73)(74)(75)(76), mesembrine (77,78), and various others AAs (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). Structures of novel AAs belonging to the I to III scaffold types (norbelladine-, cherylline-, and galantamine-type) are depicted in Figure 3, whereas types IV and V (lycorine-and homolycorine-type) are represented in Figure 4. Figure 5 displays the structures of the para-para phenol coupled AAs of the VI to IX types including crinine-, narciclasine-, tazettine-, and montanine-type. ...
... Narcipavline (6) and narcikachnine (87), two new alkaloids, were isolated, together with thirteen known alkaloids, from fresh bulbs of N. poeticus cv. Pink Parasol, their chemical structure was elucidated by MS, together with 1D and 2D NMR spectroscopic analyses, and by comparison with literature data [29]. From the fresh bulbs of N. pseudonarcissus L. cv. ...
Alkaloids are an important group of specialized nitrogen metabolites with a wide range of biochemical and pharmacological effects. Since the first publication on lycorine in 1877, more than 650 alkaloids have been extracted from Amaryllidaceae bulbous plants and clustered together as the Amaryllidaceae alkaloids (AAs) family. AAs are specifically remarkable for their diverse pharmaceutical properties, as exemplified by the success of galantamine used to treat the symptoms of Alzheimer's disease. This review addresses the isolation, biological, and structure activity of AAs discovered from January 2015 to August 2020, supporting their therapeutic interest.
... The remaining work on the genus Narcissus was in relation to Narcissus poeticus L., two studies of which have been undertaken in recent years (Havelek et al., 2017;Safratova et al., 2018). These were particularly significant since N. poeticus is one of at least six taxa of the Amaryllidaceae known to be (or have been) used for cancer treatment (Kornienko and Evidente, 2008). ...
... Encouragingly, neither homolycorine (5) nor masonine (13) (Fig. 1) were active on normal human dermal fibroblasts (NHDFs), wherein cell viabilities remained largely intact (95% and 99%, respectively) relative to the standard doxorubicin (48%) (Havelek et al., 2017). In spite of the generally poor activities observed for homolycorine and masonine, there were other alkaloids present in the plant such as lycorine (1) and Homolycorine ( Weniger et al. (1995) Homolycorine-N-oxide (9) 85.0 f Hao et al. (2013) 6-O-Methyllycorenine (10) 30 c Weniger et al. (1995) 2α-Hydroxy-9-O-demethylhomolycorine (11) >50 c Weniger et al. (1995) Dubiusine (12) >50 c Weniger et al. (1995) Masonine ( Feng et al. (2011) Masonine-N-oxide (27) 86.2 f Hao et al. (2013) 8-O-Demethylhomolycorine-N-oxide (28) 85.0 f Liu et al. (2015) 86.2 f Liu et al. (2015) (continued on next page) Oduline (14) 96% j Safratova et al. (2018) Masonine Liu et al. (2015) (continued on next page) (42) >10 Please cite this article as: J.J. Nair and J. van Staden, The plant family Amaryllidaceae as a source of cytotoxic homolycorine alkaloid principles, South African Journal of Botany (2020), https://doi.org/10.1016/j.sajb.2020.07.013 haemanthamine (3) which could substantiate the reputed use of N. poeticus in cancer treatment (Kornienko and Evidente, 2008;Havelek et al., 2017). Accordingly, the mean cell growth viabilities calculated for these compounds across the 16 cell lines were impressive at 19.9% and 20.4%, respectively (Havelek et al., 2017). ...
... The importance of the hydroxyl group becomes apparent when considering the activities of hippeastrine (7) against its dehydroxy analog masonine (13). In two independent studies masonine was shown to be a poor cytotoxic agent against as many as 16 different cell lines as indicated by cell viabilities or growth percentages which were >75% in all instances (Havelek et al., 2017;Safratova et al., 2018). By comparison hippeastrine (7) was shown to be much more potent in each of these cell lines, particularly against Jurkat (40% growth percent) and Molt4 (50% growth percent) cells . ...
Stimulated by the promising results seen for its phenanthridones in clinical trials, interest in the Amaryllidaceae as a potential source of anticancer drugs has intensified in recent years. As such, over three hundred isoquinoline principles from its various alkaloid groups have to date been screened against a large number of cancer cell lines. Whilst significant effort has been diverted towards studies of lycorine and its congeners, the closely-allied homolycorine alkaloids of this plant family have largely been overlooked. These compounds have often been used as supporting acts to bolster the diversity of structures in cytotoxicity studies of the more recognized phenanthridone, lycorane and crinane alkaloids of the Amaryllidaceae. This notwithstanding, a substantial amount of information has surfaced over the past several years on such effects for the homolycorine alkaloids. This review takes a detailed look at the cytotoxic effects manifested by over forty of these alkaloids against around sixty cell lines, which may be classified into eighteen different types of cancers. In this regard, good activities were detected for some constituents (such as lycorenine and hippeastrine) against various hepatic and prostate cancers. The structural features which support and fortify the efficacy of the homolycorine alkaloid cytotoxic pharmacophore are also considered. These include the ways in which the innate ring systems are appended as well as the size, geometry and electronics of the attendant substituents. In addition, the various mechanisms used to rationalize the cytotoxic responses are described notably, interaction with DNA, apoptosis induction, protection from tumor invasion, efflux pump perturbation and topoisomerase inhibition.
... The AA are classified into 9 main structural types (crinine, galanthamine, haemanthamine, homolycorine, lycorine, montanine, narciclasine, norbelladine, and tazettine) alongside more than 10 others (plicamine, galanthindole, augustamine, graciline, etc.). These minor structure types are usually found in trace amounts and are most often represented by single alkaloids [9,10]. Galanthamine, a selective, competitive acetylcholinesterase inhibitor with antioxidant properties is the most important AA identified so far. ...
... For commercial production of AAs, the cultivars are preferred over native species because of their availability. Some Narcissus cultivars have been already studied in detail, and a number of AAs have been isolated throughout the years [7,10,21]. From previous phytochemical studies of 40 differing Narcissus cultivars, 14 AAs were identified in the alkaloid extract of Narcissus cv. Professor Einstein [17] (see Supplementary Material). ...
... The compounds were analyzed by various spectroscopic methods (GC-MS, LC-MS, and 1D and 2D NMR spectroscopy) and identified by comparison with literature data as masonine (1) [22], homolycorine (2) [23], ismine (3) [24], caranine (4) [25], galanthamine (5) [26], narwedine (6) [27], lycoraminone (7) [28], pluviine (8) [25], incartine (9) [29], galanthine (10) [30], lycoramine (11) [26], epinorgalanthamine (12) [31], norlycoramine (13) [32], haemanthamine (14) [32], hippeastrine (15) [33], epimaritidine (16) [34], lycorine (17) [35], tazettine (18) [36], eugenine (19) [37], norpluviine (20) [38], 9-O-demethylmaritidine (21) [39], pancracine (22) [40], and 9-O-demethylhomolycorine (23) [23] (Figure 1). The alkaloids that were isolated were representatives of the homolycorine (1, 2, 15, 19, 23), galanthamine (5, 6, 7, 11, 12, 13), haemanthamine (14,16,21), lycorine (4,8,9,10,17,20), montanine (22), tazettine (18), and miscellaneous (3) structure types. ...
In this detailed phytochemical study of Narcissus cv. Professor Einstein, we isolated 23 previously known Amaryllidaceae alkaloids (1–23) of several structural types and one previously undescribed alkaloid, 7-oxonorpluviine. The chemical structures were identified by various spectroscopic methods (GC-MS, LC-MS, 1D, and 2D NMR spectroscopy) and were compared with literature data. Alkaloids which had not previously been isolated and studied for cytotoxicity before and which were obtained in sufficient amounts were assayed for their cytotoxic activity on a panel of human cancer cell lines of different histotype. Above that, MRC-5 human fibroblasts were used as a control noncancerous cell line to determine the general toxicity of the tested compounds. The cytotoxicity of the tested alkaloids was evaluated using the WST-1 metabolic activity assay. The growth of all studied cancer cell lines was inhibited by pancracine (montanine-type alkaloid), with IC50 values which were in the range of 2.20 to 5.15 µM.
... The activities for ambelline and 11-O-acetylambelline are in this instance noteworthy since they previously were shown to be ineffective against both resistant (FAC8) and sensitive (NF54 and D10) strains of P. falciparum [15,17,19]. In terms of selectivity all four compounds (17,19,24,25) exhibited poor cytotoxicities against the A2780 ovarian cancer cell line (IC 50 s > 20 μg/mL), indicating that the activities observed against P. falciparum Dd2 were due to direct antiplasmodial effects rather than to cell toxicity [20]. ...
... However, in the subsequent antiprotozoal screen neither compound exhibited any activity towards P. falciparum strains NF54 and K1 [24]. Haemanthamine (26) from bulbs of Narcissus poeticus L. displayed no discernible activity against Plasmodium berghei (IC 50 > 30 μg/mL) [25]. This is the only case found in the literature where a crinane alkaloid has been tested against a malarial parasite other than P. falciparum [25]. ...
... Haemanthamine (26) from bulbs of Narcissus poeticus L. displayed no discernible activity against Plasmodium berghei (IC 50 > 30 μg/mL) [25]. This is the only case found in the literature where a crinane alkaloid has been tested against a malarial parasite other than P. falciparum [25]. P. berghei which is transmitted by Anopheles mosquitoes is amongst the four Plasmodium species known to cause malaria in African murine rodents, the others being P. chabaudi, P. vinckei and P. yoelii [25]. ...
Malaria is prevalent in tropical and subtropical regions of the globe. With over 200 million cases reported annually, particularly in sub-Saharan Africa, it is an unnecessary burden to already overworked and ailing healthcare structures. Traditional medicine (TM) remains vibrant in most of these regions wherein plants often serve as the first line of defense against malaria. Given this fact as well as the successes elsewhere of therapies such as Artemisia annua emanating from evidence-based TM, interest in plants as a source of new antimalarial drugs has been rejuvenated. The bulbous plant family Amaryllidaceae is recognized for its structurally-diverse alkaloid constituents which exhibit interesting biological properties. This review focuses on the in vitro activities demonstrated by its crinane alkaloids against various strains of the malaria-causing parasite Plasmodium falciparum. The survey embraces the twelve genera of the Amaryllidaceae whose nineteen representative species have been examined for antiplasmodial crinane alkaloid principles. A total of seventy-two compounds were screened against nine strains of P. falciparum, with the α-crinanes reflecting better overall activities than their corresponding β-crinane subgroup congeners. In terms of potency, an ED 50 of 0.14 μg/mL (for augustine in the D-6 strain) and IC 50 of 0.35 μg/mL (for haemanthidine in the K1 strain) were the lowest activity indices observed. Structure-activity relationship studies afforded useful insight on the antiplasmodial pharmacophore and the features supporting its efficacy. Overall, crinane alkaloids have provided a useful platform for the study of antiplasmodial effects, not only in terms of potency but also in terms of structural diversity.
... Next, the chemical structures are increasingly elucidated by MS and 1D and 2D NMR spectroscopic analyses. Such an approach was presented by Safratova [23] whose study allowed her to isolate as many as 15 alkaloids of which two had been unidentified so far [23]. In turn, Borra et al. [24] developed and optimized an alternative protocol for the isolation of narciclasine from Amaryllidaceae bulbs. ...
... Next, the chemical structures are increasingly elucidated by MS and 1D and 2D NMR spectroscopic analyses. Such an approach was presented by Safratova [23] whose study allowed her to isolate as many as 15 alkaloids of which two had been unidentified so far [23]. In turn, Borra et al. [24] developed and optimized an alternative protocol for the isolation of narciclasine from Amaryllidaceae bulbs. ...
Alkaloids obtained from plants belonging to the Amaryllidaceae and Lycopodiaceae families are of great interest due to their numerous properties. They play a very important role mainly due to their strong antioxidant, anxiolytic and anticholinesterase activities. The bioactive compounds obtained from these two families, especially galanthamine and huperzine A, have found application in the treatment of the common and incurable dementia-like Alzheimer’s disease. Thanks to this discovery, there has been a breakthrough in its treatment by significantly improving the patient’s quality of life and slowing down disease symptoms – albeit with no chance of a complete cure. Therefore, a continuous search for new compounds with potent anti-AChE activity is needed in modern medicine. In obtaining new therapeutic bioactive phytochemicals from plant material, the isolation process and its efficiency are crucial. Many techniques are known for isolating bioactive compounds and determining their amounts in complex samples. The most commonly utilized methods are extraction using different variants of organic solvents allied with chromatographic and spectrometric techniques. Optimization of these methods and modification of their procedures potentially allows researchers to obtain the expected results. The aim of this paper is to present known techniques for the isolation of alkaloids, especially from three species Narcissus, Lycopodium and Huperzia that are a rich source of AChE inhibitors. In addition, innovative combinations of chromatographic and spectrometric methods and novel TLC-bioautography will be presented to enable researchers to better study the bioactivity of alkaloids.
... The ESI-HRMS of 2 showed a molecular ion peak [M + H] + at m/z 541.2707, corresponding to the formula C33H37N2O5 + (calculated 541.2697). According to our previous structural elucidations of narcikachnine-type AAs, narciabduliine 2 showed great structural similarity with narcieliine [8,10,11]. A diastereomeric mixture of atropisomers in a 1:1.1 ratio was identified as well (see Figure S11, Supplementary Materials). ...
... This structural type of AA is a combination of galantamine and galanthindole cores. Recently, several alkaloids of this structural type isolated from Amaryllidaceae plants by our group demonstrated interesting hBuChE inhibition activity [7,8,10,11]. Compared with previously isolated narcikachnine-type AAs, the new alkaloid, narciabduliine (2), demonstrated balanced hAChE/hBuChE inhibition activity with an IC50 value of 3.24 ± 0.73 μM for hAChE and 3.44 ± 0.02 μM for hBuChE (Figures 3 and 4, respectively). ...
Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.
... In the current study, nine AAs of various structural types isolated previously from different Amaryllidaceae plants (except 3-O-methylpancracine, which has been synthesized within the current study; Figure 4) [19,20,24], along with 30 newly synthesized derivatives of galanthamine (1a-1s), 3-O-methylpancracine (3a-3g), vittatine (4a-4b) and maritidine (5a-5b) have been screened for their antimycobacterial activity against three different mycobacterial strains: M. tuberculosis H37Ra, M. aurum and M. smegmatis. The last two are fast-growing strains that do not cause tuberculosis in humans, but are much safer to handle. ...
The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and mari-tidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepa-tocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galan-thamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index .
... also exhibited weak anti-human AChE activity.99 (+)-Parfumidine (79), a spirobenzylisoquinoline alkaloid, exhibited POP inhibitory activity with an IC 50 value of 99 µM, compared with 3.27 µM for the positive drug (Z)-pro-prolinal.24 ...
Isoquinoline alkaloids, an important class of N‐based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014–2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti‐inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.
... In plant breeding programs, N. poeticus is a parent form in obtaining multi-flowered hybrids and large-cupped narcissi [4]. It found an application in the pharmaceutical industry as a source of biologically active compounds, such as alkaloids, including galantamine [5], which alleviates the symptoms of Alzheimer's disease [6]. Bulbs of Narcissus poeticus are also a source of narpoetan-a growth-stimulating substance recommended for pre-sowing treatment of spiked cereals and cotton in order to stimulate seedlings growth [7]. ...
Geophytes are an increasingly widely used group of plants. Its high biodiversity, however, significantly impacts the cultivation process. Therefore, every new insight into the behavioral aspects of each single species is crucial for production. This study, for the first time, aims at contributing to a better understanding of the interplay between the bulb size potential of Narcissus poeticus and the pattern of bulb lifting time to find the optimal combination of these factors in obtaining the best quality propagation material. Twelve bulb size groups were examined. Plants were planted in the open air in two locations of Central East Europe and lifted in three terms: immediately and two and four weeks after flowering. Bulb fresh and dry weight, as well as leaf, root and total plant dry weight, increased with growing bulb size and delayed the time of lifting. The bulb weight increase indicator was twice as high for bulbs lifted in the third date compared to those lifted earlier. Its value was the highest for the smallest bulbs. Bulb shape ratio gradually decreased together with the increase of bulb weight and later lifting term. Principal components analysis allowed singling out two principal components that accounted for 86.58% of total variability.
... The connection between OpB and the parasite suggests that it is a key point in the host infection [19], being a promising target for the development of new antileishmanial drugs. Other studies have shown that alkaloids can significantly inhibit the activity of oligopeptidases [20][21][22]. However, the inhibitory activity of various alkaloids has not yet been evaluated. ...
Chemotherapy is limited in the treatment of leishmaniasis due to the toxic effects of drugs, low efficacy of alternative treatments, and resistance of the parasite. This work assesses the in vitro activity of flavopereirine on promastigote cultures of Leishmania amazonensis. In addition, an in silico evaluation of the physicochemical characteristics of this alkaloid is performed. The extract and fractions were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid identified by NMR. The antileishmanial activity and cytotoxicity were assayed by cell viability test (MTT). The theoretical molecular properties were calculated on the Molinspiration website. The fractionation made it possible to isolate a beta-carboline alkaloid (flavopereirine) in the alkaloid fraction. Moreover, it led to obtaining a fraction with greater antileishmanial activity, since flavopereirine is very active. Regarding the exposure time, a greater inhibitory effect of flavopereirine was observed at 24 h and 72 h (IC50 of 0.23 and 0.15 μg/mL, respectively). The extract, fractions, and flavopereirine presented low toxicity, with high selectivity for the alkaloid. Furthermore, flavopereirine showed no violation of Lipinski’s rule of five, showing even better results than the known inhibitor of oligopeptidase B, antipain, with three violations. Flavopereirine also interacted with residue Tyr-499 of oligopeptidase B during the molecular dynamics simulations, giving a few insights of a possible favorable mechanism of interaction and a possible inhibitory pathway. Flavopereirine proved to be a promising molecule for its antileishmanial activity.
... All Amaryllidaceae alkaloids tested have been previously isolated at the Department of Pharmaceutical Botany, Faculty of Pharmacy in Hradec Králové from various Amaryllidaceae plant species (Zephyranthes robusta [39,40], Chlidanthus fragrans [27,41], Nerine bowdenii [42], Narcissus poeticus cv. Pink Parasol [43], and N. poeticus cv. Brackenhurst [44]). ...
Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}.
We report the first asymmetric total synthesis of recently isolated heterodimeric Amaryllidaceae alkaloids, narcipavlines A (1a) and B (1b), and narcikachnines A (2a) and B (2b), thereby confirming their absolute stereochemistry. These alkaloids showcase a unique heterodimeric structure, amalgamating two distinct types of Amaryllidaceae alkaloids: the cis-hydrodibenzofuran containing tetracyclic galantamine core (6a) and the galanthindole core (7) featuring a biaryl axis. The presence of this biaryl axis, coupled with the substantial galantamine core (6a) at the ortho substituents, imposes constraints on free rotation around the C–C axis, resulting in atropisomerism, an exceedingly rare phenomenon in nature. Key steps in the synthesis encompass the utilization of a one-pot double reductive amination approach for the establishment of C–N–C bonds to merge both the galantamine (6a) and galanthindole (7) cores. Additionally, the Mitsunobu reaction and intramolecular Heck cyclization have emerged as pivotal techniques for crafting the tricyclic hydrodibenzofuran core [(−)-13], incorporating an all-carbon quaternary stereogenic center.
Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of plant alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood–brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.
Geophytes are plants of high biological diversity that depends to a great extent on the growing process. Based on what is stated, any new method of production of Narcissus L. has a decisive effect on its production. The aim of the study is to determine if it is possible to achieve better economic-agricultural results with a new method/form of plant growing (Narcissus L., Amaryllidaceae). Under the conditions of the Pannonian environment the production of two methods/forms of growing is compared. By measuring physical plant parameters (p=.00) the results show that the production is better using the standard method of growing. The realized value on the market is higher for the plants grown using the standard method of production (p<.05). The contribution of the author of the study is to indicate a new way of growing, which leads to a higher total value of production.
Medicinal plants are of interest for human uses from prehistoric times to the present day in many parts of the world. At the same time, the importance and demand for these plants are always continuous. Herbal-based drugs, pharmaceuticals, health products, food additives, and cosmetics can make significant contributions to the economy. In addition, they are an alternative economic supply chains for developing countries’ economies. Medicinal plants contain a wide variety of active substances that are used in the treatment of various ailments by almost the entire population of the world. Chemical analyses of medicinal plant materials are performed, and their individual chemical compounds and plant secondary metabolites (PSMs) are characterized after isolation. After the procedure, the identified chemical entities are tested for their pharmacological activities and therapeutics. Medicinal plant’s pharmacological properties are usually often predicted based on their chemical structures. Many pharmacological studies have shown that several medicinal plants exhibit a wide range of biological activity, and the plant species contain many bioactive compounds such as coumarins, terpenoids, and glycosides responsible for a collection of pharmacological properties. The VOSviewer tool was used to visualize the results. The documents including medicinal plants in “article title, abstract, keywords,” but limited to containing the topic “pharmacological properties” were extracted from the Scopus database. Briefly, the research was done using medicinal plants in “article title, abstract, keywords” and then 175,818 documents were retrieved. The second step was the limitation of the results to “pharmacological properties,” i.e., 2715 document numbers and 400,000 plant species were limited. Herewith the chapter, we herein are concerned with the evaluation of medicinal plants for their pharmacological properties.KeywordsTherapeuticsPharmacologicalBioactive compoundsSecondary metabolites
Alzheimer's disease is a chronic neurodegenerative condition that affects mainly memory and other cognitive functions. Interest in finding treatments effective for this disease has increased in recent years, leading to the investigation of the use of medicinal plants and isolated compounds as possible therapeutic treatments. This study aims to identify research on plants and isolated compounds that demonstrate efficacy in the treatment of markers of Alzheimer's pathology over the years. To achieve this goal, we performed a literature review using methods quantitative, which allows us to identify trends, authors, journals and research areas most relevant to the topic. We collect data and submit them to quantitative analyzes to get an overview of the state of the art in this particular field. The methodology employed included the use of bibliometric software for surveys quantitative surveys and the Rayyan platform for qualitative surveys. The quantitative analysis covered the leadership of the studies, the power analysis used in the articles and the identification of predominant themes. While in the qualitative analysis, we focused on the experimented plants that cause anti-Alzheimer's effects, with a focus on the isolated chemical compounds responsible by pharmacological action. As a result of the quantitative analysis, we found a growing interest in research on plants and Alzheimer's disease. Since the first publications at the beginning of the 2000s to the present day, there has been a steady increase in the number of studies, reflecting a significant progress has been made in understanding the possible benefits of plants in the treatment and in preventing this debilitating disease. Our findings highlight the continuing importance of research in this area, which may provide promising therapeutic alternatives to face the challenges posed by the disease of Alzheimer's. Through this bibliographic research, we hope to contribute to the advancement of scientific knowledge and for the development of more effective therapeutic approaches and accessible for this complex condition.
Geophytes are plants of high biological diversity that depends to a great extent on the growing process. Based on what is stated, any new method of production of Narcissus L. has a decisive effect on its production. The aim of the study is to determine if it is possible to achieve better economic-agricultural results with a new method/form of plant growing (Narcissus L., Amaryllidaceae). Under the conditions of the Pannonian environment the production of two methods/forms of growing is compared. By measuring physical plant parameters (p=.00) the results show that the production is better using the standard method of growing. The realized value on the market is higher for the plants grown using the standard method of production (p<.05). The contribution of the author of the study is to indicate a new way of growing, which leads to a higher total value of production.
In this paper, authors started from the hypothesis that innovations contribute to creativity and that children become more aware of in what way they can contribute to the development of rural areas. With children, play is important, and games that strengthen the imagination and encourage children to think for themselves are one of the best ways to encourage making future, strategic decisions. The challenge was to test the game “Tesla” on older school age children from 12 to 14 years old from rural areas. 138 children from five rural schools on Fruška Gora were examined. The results showed that children from rural areas, with the help of smart devices, played the game at the same level as children from any world metropolis. What’s more, through the game, the children showed awareness of the importance of the village, staying in the village and what is needed for the village to “live”.
The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1–28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of the β-crinane alkaloid ambelline (28a–28t) and eleven derivatives of the α-crinane alkaloid haemanthamine (29a–29k) against the hepatic stage of Plasmodium infection. Six of these derivatives (28h, 28m, 28n and 28r–28t) were newly synthesized and structurally identified. The most active compounds, 11-O-(3,5-dimethoxybenzoyl)ambelline (28m) and 11-O-(3,4,5-trimethoxybenzoyl)ambelline (28n), displayed IC50 values in the nanomolar range of 48 and 47 nM, respectively. Strikingly, the derivatives of haemanthamine (29) with analogous substituents did not display any significant activity, even though their structures are quite similar. Interestingly, all active derivatives were strictly selective against the hepatic stage of infection, as they did not demonstrate any activity against the blood stage of Plasmodium infection. As the hepatic stage is a bottleneck of the plasmodial infection, liver-selective compounds can be considered crucial for further development of the malaria prophylactics.
This article aims to provide an updated description and comparison of the data currently available in the literature (from the last 15 years) on the studied natural inhibitors of cholinesterases (IChEs), namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These data also apply to the likely impact of the structures of the compounds on the therapeutic effects of available and potential cholinesterase inhibitors. IChEs are hitherto known compounds with various structures, activities and origins. Additionally, multiple different methods of analysis are used to determine the cholinesterase inhibitor potency. This summary indicates that natural sources are still suitable for the discovery of new compounds with prominent pharmacological activity. It also emphasizes that further studies are needed regarding the mechanisms of action or the structure-activity correlation to discuss the issue of cholinesterase inhibitors and their medical application.
Background:
Hippeastrum species have a wide range of biological properties. In Argentina, this genus comprises ten widely distributed species.
Purpose:
To evaluate the antiparasitic and anticholinesterase activities and chemical profiles of seven Argentinean Hippeastrum species and determine the synergism between the major isolated alkaloid-montanine-and benznidazole in anti-Trypanosoma cruzi activity.
Methods:
The antiparasitic activity was evaluated through antiproliferative and viability assays against T. cruzi epimastigotes. Synergism assays were performed using the Chou-Talalay method. AChE and BuChE inhibitory activities were also assessed. The alkaloid composition was obtained using GC-MS analysis.
Results:
All extracts showed strong growth inhibition of T. cruzi epimastigote proliferation. The extracts from H. aglaiae, H. aulicum, and H. hybrid stand out for their potent and total growth inhibition, which was comparable to benznidazole. The H. reticulatum extract showed strong Acetylcholinesterase (AChE) inhibitory activities, while five species showed moderate Butyrylcholinesterase (BuChE) inhibition. Fifteen alkaloids were identified by means of GC-MS. Regarding the synergism assessment, the highest synergistic effect was obtained from the combination of montanine and benznidazole.
Conclusion:
Hippeastrum species bulb extracts from Argentina were shown to be a good source of antiparasitic alkaloids and cholinesterase inhibitors. The synergism between montanine and benznidazole emerges as a potential combination for future studies to treat Chagas disease.
Plant biodiversity is an important source of compounds with medicinal properties. The alkaloid galanthamine, first isolated from Galanthus woronowii (Amaryllidaceae), is approved by the FDA for the palliative treatment of mild to moderate Alzheimer’s disease due to its acetylcholinesterase (AChE) inhibitory activity. Obtaining this active pharmaceutical ingredient, still sourced on an industrial scale from the Amaryllidaceae species, is a challenge for pharmaceutical companies due to its low natural yield and the high cost of its synthesis. The aim of this work was to determine the alkaloid profile of three different Rauhia (Amaryllidaceae) species collected in Peru, and to assess the potential application of their extracts for the treatment of Alzheimer’s disease. The alkaloids were identified by gas chromatography coupled to mass spectrometry (GC-MS), and the AChE inhibitory activity of the extracts was analyzed. Thirty compounds were quantified from the Rauhia species, the R. multiflora extract being the most interesting due to its high diversity of galanthamine-type structures. The R. multiflora extract was also the most active against AChE, with the half maximal inhibitory concentration (IC50) values of 0.17 ± 0.02 μg·mL−1 in comparison with the IC50 values of 0.53 ± 0.12 μg·mL−1 for galanthamine, used as a reference. Computational experiments were carried out on the activity of the galanthamine-type alkaloids identified in R. multiflora toward five different human AChE structures. The simulation of the molecules 3-O-acetylgalanthamine, 3-O-acetylsanguinine, narwedine, and lycoraminone on the 4EY6 crystal structure theoretically showed a higher inhibition of hAChE and different interactions with the active site compared to galanthamine. In conclusion, the results of this first alkaloid profiling of the Rauhia species indicate that R. multiflora is an important natural source of galanthamine-type structures and could be used as a model for the development of biotechnological tools necessary to advance the sustainable production of galanthamine.
Clivia miniata (Amaryllidaceae) is an herbaceous evergreen flowering plant that is endemic to South Africa and Swaziland and belongs to one of the top-10 traded medicinal plants in informal medicine markets in South Africa. The species has been reported as the most important component of a traditional healer’s pallet of healing plants. Eighteen known Amaryllidaceae alkaloids (AAs) of various structural types, and one undescribed alkaloid of homolycorine-type, named clivimine B (3), were isolated from Clivia miniata. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR techniques and by comparison with literature data. Compounds isolated in a sufficient quantity, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibition activities.
Narciindole A, the first representative of Amaryllidaceae alkaloids with an indol-3-ylmethanone framework, was isolated from bulbs of Narcissus pseudonarcissus (L.) cv. Carlton, together with carltonine D and carltonine E, which share the same unusual structural motif as dimeric carltonine C (reported in 2020), exhibiting atropisomerism. Unambiguous structure elucidations have been achieved by NMR spectroscopy, HRMS, and comparison with literature data of related alkaloids. Furthermore, the chirality of known alkaloids with a galanthindole biaryl core was revised using optical rotation. Last, but not least, a biosynthetic pathway for dimeric carltonine-type alkaloids was proposed. Unfortunately, in terms of biological activity, the isolated alkaloids showed only moderate inhibition of human acetylcholinesterase and/or butyrylcholinesterase.
Natural products have always played a significant role in the search for new drugs. One of the most relevant alkaloid-containing plant groups is the Amaryllidaceae family, a source of exclusive structures with a wide variety of pharmacological activities. The aim of this work was to determine the alkaloid composition and biological potential of an extract from the bulbs of an endemic Peruvian Amaryllidaceae species Ismene amancaes (Ker Gawl.) Herb. The alkaloid profiling was carried out by GC-MS, which revealed the presence of 13 compounds, 2 of them unidentified. The plant extract was found to contain high amounts of lycoramine, a galanthamine-type alkaloid. The extract also presented low inhibitory potential against the enzymes AChE and BuChE, with IC50 values of 14.6 ± 0.6 and 37.6 ± 1.4 μg·mL−1, respectively, and good to moderate inhibitory activity against the protozoan Plasmodium falciparum strain FCR-3 (chloroquine-resistant), with IC50 values of 3.78 ± 0.3 μg·mL−1. This is the first report of the alkaloid profile of a plant of the Ismene genus, which could be an interesting source of bioactive compounds.
The flowers of Narcissus poeticus are used for the isolation of valuable fragrance substances. So far, as the majority of these substances consist of volatile and sensitive to heat compounds, there is a need of developing effective methods for their recovery. In this study, freeze-dried N. poeticus inflorescences were extracted with pure supercritical CO2 (SFE-CO2) and its mixture with 5% co-solvent ethanol (EtOH) at 40 °C. Extract yields varied from 1.63% (12 MPa) to 3.12% (48 MPa, 5% EtOH). In total, 116 volatile compounds were identified by GC-TOF/MS in the extracts, which were divided into 20 different groups. Benzyl benzoate (9.44–10.22%), benzyl linoleate (1.72–2.17%) and benzyl alcohol (0.18–1.00%) were the major volatiles among aromatic compounds. The amount of the recovered benzyl benzoate in N. poeticus SFE-CO2 extracts varied from 58.98 ± 2.61 (24 MPa) to 91.52 ± 1.36 (48 MPa) mg/kg plant dry weight (pdw). α-Terpineol dominated among oxygenated monoterpenes (1.08–3.42%); its yield was from 9.25 ± 0.63 (12 MPa) to 29.88 ± 1.25 (48 MPa/EtOH) mg/kg pdw. Limonene was the major monoterpene hydrocarbon; (3E)-hexenol and heneicosanol dominated among alcohols and phenols; dihydroactinidiolide and 4,8,12,16-tetramethyl heptadecan-4-olide were the most abundant lactones; heptanal, nonanal, (2E,4E)-decadienal and octadecanal were the most abundant aldehydes. The most important prenol lipids were triterpenoid squalene, from 0.86 ± 0.10 (24 MPa) to 7.73 ± 0.18 (48 MPa/EtOH) mg/kg pdw and D-α-tocopherol, from 1.20 ± 0.04 (12 MPa) to 15.39 ± 0.31 (48 MPa/EtOH) mg/kg pdw. Aliphatic hydrocarbons (waxes) constituted the main part (41.47 to 54.93%) in the extracts; while in case of a 5% EtOH the percentage of alkanes was the lowest. The fraction of waxes may be removed for the separation of higher value fragrance materials. In general, the results obtained are promising for a wider application of SFE-CO2 for the recovery of fragrance substances from N. poeticus flowers.
Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease recognized as the most common form of dementia among elderly people. Due to the fact that the exact pathogenesis of AD still remains to be fully elucidated, the treatment is only symptomatic and available drugs are not able to modify AD progression. Considering the increase in life expectancy worldwide, AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. Due to their complex nitrogen-containing structures, alkaloids are considered to be promising candidates for use in the treatment of AD. Since the introduction of galanthamine as an antidementia drug in 2001, Amaryllidaceae alkaloids (AAs) and further isoquinoline alkaloids (IAs) have been one of the most studied groups of alkaloids. In the last few years, several compounds of new structure types have been isolated and evaluated for their biological activity connected with AD. The present review aims to comprehensively summarize recent progress on AAs and IAs since 2010 up to June 2021 as potential drugs for the treatment of AD.
A new indole alkaloid (1), together with eight known indole alkaloid derivatives (2–9), was isolated from Hosta plantaginea for the first time. The structures of compounds 1–9 were elucidated on the basis of comprehensive spectroscopic analyses and references. Compounds 1–9 were evaluated for their inhibition of steroid 5α-reductase activity in vitro. Among them, compounds 1 and 2 showed important inhibition of steroid 5α-reductase activities.
Fourteen (1–14) known Amaryllidaceae alkaloids, of various structural types, have been isolated from fresh bulbs of Hippeastrum X hybridum cv. Ferrari. The chemical structures were identified by various spectroscopic (1D and 2D NMR) and mass spectrometric (GC–MS, LC-MS) methods, and by comparison with literature data. Isolated alkaloids which, up to this date have not been studied for their inhibition potency against AChE, BuChE and POP, were screened in vitro for these inhibition activities. Unfortunatelly, all natural alkaloids were inactive in the AChE/BuChE assay; only zephyranthine (14) displayed moderate inhibition activity agains POP with an IC50 value of 142 ± 10 µM. Moreover, twelve new derivatives of the haemanthamine-type alkaloid vittatine (7), isolated in gram amounts from Hippeastrum cv. Ferrari, have been designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the tested compounds revealed an intriguing selective hBuChE inhibitory profile with single-digit micromolar IC50 values. The strongest hBuChE inhibition was demonstrated by 3-O-(2-methylbenzoyl)vittatine (7b), 3-O-(2-nitrobenzoyl)vittatine (7h) and 3-O-(2-chlorbenzoyl)vittatine (7m) with IC50 values 8.0 ± 0.1 µM, 1.4 ± 0.1 µM and 5.4 ± 0.1 µM, respectively. The mode of hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 7b-, 7h-, and 7m-hBuChE complexes.
Thirteen known (1–12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13–15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.
Plants of the Amaryllidaceae family, have a wide distribution through both tropical and sub-tropical regions of the world. They have also a long and notable place in the history of traditional and Western medicine. Amaryllidaceae alkaloids are a structurally diverse group of plant metabolites with a wide range of biological properties including antimalarial, antitumor, antimicrobial, antiviral, enzyme inhibitory, antioxidant, anticonvulsant and antifungal activities. Among them, the haemanthamine-type alkaloids, which have the 5,10b-ethanophenanthridine skeleton as the core structure, represented by haemanthamine and haemanthidine, have received considerable attention, since they have been reported to possess antitumor properties. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids haemanthamine and haemanthidine.
Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3β (GSK-3β) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.
Abstract
Narcissus spp. are an economically important crop for medicines in relation with the alkaloids production, mainly galanthamine, an acetylcholinesterase inhibitor used for the treatment of Alzheimer’s disease. In this article an extensively study of the phytochemistry of both bulbs of different species and varieties of Narcissus grown in Iran and in vitro culture of these plants was investigated. In particular, the Amaryllidaceae alkaloid profile and the galanthamine and lycorine contents in wild bulbs of Narcissus papyraceus (G5) and four varieties of Narcissus tazetta (N. tazetta var. Shahla (G4), N. tazetta var. Shastpar (G1), N. tazetta var. Meskin (G2), N. tazetta var. Panjehgorbei (G3)), growing in Iran are reported. The alkaloid profiles were investigated by GC–MS and LC–MS and the quantitative analysis was performed using GC–MS. In total, thirty alkaloids were identified among them nine alkaloids were observed with the both methods of analysis. The variety Meskin of N. tazetta (G2), showed the highest diversity of alkaloids and the highest content in galanthamine. On this last species (G2) and on N. tazetta var. Shahla (G4), the effects of auxins 2,4-dichlorophenoxyacetic acid (2,4-D), 4-amino-3,5,6-trichloropicolinic acid (Picloram) and naphthalene acetic acid (NAA) at concentrations of 25 and 50 μM were studied on the induction of callus and its capacity to induce organogenesis and alkaloid diversity. All auxins, at the concentrations of 25 and 50 μM, produced calli. Bulblets and roots were formed on calli grown only in the presence of 25 or 50 μM NAA. GC–MS analyses showed the presence of galanthamine and lycorine in calli, roots and bulblets, with all auxins whatever the concentration used while demethylmaritidine and tazettine were found in differentiated tissue cultures cultivated on the medium containing NAA (25 or 50 μM) or in calli initiated with Picloram (50 μM). Precursor 4’-O-methylnorbelladine (MN) of Amaryllidaceae alkaloids feeding was found to significantly improve the accumulation of both galanthamine (82 μg/g DW) and lycorine (1800 μg/g DW) in bulblets of N. tazetta var. Meskin (G2).
Twelve derivatives 1a–1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds’ plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.
Haemanthus humilis Jacq., an indigenous South African Amaryllidaceae, was studied for the first time for its alkaloid content. From the acid extract of its bulbs, albomaculine, incartine, coccinine and montanine, belonging to the lycorine-, homolycorine- and isoquinoline-type alkaloids respectively, were isolated. Coccinine was the main metabolite (1.49 g/kg) and to the best of our knowledge H. humilis is to date the best natural source of this alkaloid. It is noteworthy that this Amaryllidaceae does not synthesize lycorine, the main and most common alkaloid produced by this plant genus. All the isolated alkaloids were bio-assayed for their anticancer activity against a panel of six human cancer cell lines, with coccinine evaluated for the first time. The results showed that coccinine and montanine have significant activity at low micromolar concentrations.
Ongoing studies of Zephyranthes robusta resulted in the isolation of the lycorine-type alkaloid previously called carinatine and 10-O-demethylgalanthine. The NMR data given previously for this compound were revised and completed by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. The name of the isolated compound was corrected to 9-O-demethylgalanthine in accordance with the currently used system of numbering of lycorine-type alkaloids. 9-O-Demethylgalanthine and galanthine, a previously isolated alkaloid from Z robusta, were inactive in acetylcholinesterase/butyrylcholinesterase assays (IC50 > 500 microM), but showed important prolyl oligopeptidase inhibition activity.
Aim
To study the Amaryllidaceae alkaloids of the bulbs of Lycoris radiata.
Methods
The chemical constituents were isolated and purified by various chromatographic techniques, and the chemical structures were elucidated on the basis of spectroscopic methods. In addition, the antiviral activities of alkaloids 1–10 were evaluated using flu virus A.
Results
One new homolycorine-type alkaloid 2α-methoxy-6-O-ethyloduline (1), together with nine known alkaloids 2α-methoxy-6-O-methyloduline (2), trispherine (3), 8-O-demethylhomolycorine (4), homolycorine (5), 9-O-demethylhomolycorine (6), oduline (7), lycorenine (8), 6α-O-methyllycorenine (9) and O-ethyllycorenine (10) were obtained.
Conclusion
Alkaloid 1 is a new compound, and 1–3 were major alkaloids in this plant. Alkaloids 1–3 showed weak antiviral activities against flu virus A with IC50 values of 2.06, 0.69, and 2.71 μg·mL-1 and CC50 values of 14.37, 4.79, and 80.12 μg·mL-1, respectively.
The Amaryllidaceae alkaloids represent a large (over 300 alkaloids have been isolated) and still expanding group of biogenetically related isoquinoline alkaloids that are found exclusively in plants belonging to this family. In spite of their great variety of pharmacological and/or biological properties, only galanthamine is used therapeutically. First isolated from Galanthus species, this alkaloid is a long-acting, selective, reversible and competitive inhibitor of acetylcholinesterase, and is used for the treatment of Alzheimer's disease. Other Amaryllidaceae alkaloids of pharmacological interest will also be described in this chapter.
Many persons with Alzheimer's disease (AD) treated with galantamine appear to receive additional cognitive benefit from citalopram. Both drugs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These enzymes co-regulate acetylcholine catabolism. In AD brain, AChE is diminished while BuChE is not, suggesting BuChE inhibition may be important in raising acetylcholine levels. BuChE is subject to activation at high acetylcholine levels reached at the synaptic cleft. The present study explores one way combining galantamine and citalopram could be beneficial in AD.
Spectrophotometric studies of BuChE catalysis in the absence or presence of galantamine or citalopram or both, were performed using the Ellman method. Data analysis involved expansion of our previous equation describing BuChE catalysis.
Galantamine almost completely inhibited BuChE at low substrate concentrations (V(S)=43.6 μM/min; V(S(gal))=0.34 μM/min) without influencing the substrate-activated form of the enzyme (V(SS)=64.0 μM/min;V(SS(gal))=62.3 μM/min). Conversely, citalopram inhibited both un-activated (V(S)=43.6 μM/min; V(S(cit))=10.2 μM/min) and substrate-activated (V(SS)=64.0 μM/min; V(SS(cit))=47.3 μM/min) forms of BuChE. Combined galantamine and citalopram increased inhibition of un-activated BuChE (V(S)=43.6 μM/min; V(S(gal)(cit))=2.73 μM/min) and substrate-activated form (V(SS)=64.0 μM/min; V(SS(gal)(cit))=42.2 μM/min).
Citalopram and galantamine produce a combined inhibition of BuChE that is considered to be synergistic.
Clinical benefit from combined galantamine and citalopram may be related to a synergistic inhibition of BuChE, facilitating cholinergic neurotransmission. This emphasizes the importance of further study into use of drug combinations in AD treatment.
The quantitative analysis of Plasmodium development in the liver in laboratory animals in cultured cells is hampered by low parasite infection rates and the complicated methods required to monitor intracellular development. As a consequence, this important phase of the parasite's life cycle has been poorly studied compared to blood stages, for example in screening anti-malarial drugs. Here we report the use of a transgenic P. berghei parasite, PbGFP-Luccon, expressing the bioluminescent reporter protein luciferase to visualize and quantify parasite development in liver cells both in culture and in live mice using real-time luminescence imaging. The reporter-parasite based quantification in cultured hepatocytes by real-time imaging or using a microplate reader correlates very well with established quantitative RT-PCR methods. For the first time the liver stage of Plasmodium is visualized in whole bodies of live mice and we were able to discriminate as few as 1–5 infected hepatocytes per liver in mice using 2D-imaging and to identify individual infected hepatocytes by 3D-imaging. The analysis of liver infections by whole body imaging shows a good correlation with quantitative RT-PCR analysis of extracted livers. The luminescence-based analysis of the effects of various drugs on in vitro hepatocyte infection shows that this method can effectively be used for in vitro screening of compounds targeting Plasmodium liver stages. Furthermore, by analysing the effect of primaquine and tafenoquine in vivo we demonstrate the applicability of real time imaging to assess parasite drug sensitivity in the liver. The simplicity and speed of quantitative analysis of liver-stage development by real-time imaging compared to the PCR methodologies, as well as the possibility to analyse liver development in live mice without surgery, opens up new possibilities for research on Plasmodium liver infections and for validating the effect of drugs and vaccines on the liver stage of Plasmodium.
A new indole alkaloid, galanthindole, was isolated from Galanthus plicatus ssp. byzantinus (Amaryllidaceae), a plant native to northwestern Turkey. Incorporating a non-fused indole ring, galanthindole may represent the prototype of a new subgroup of the Amaryllidaceae alkaloids. Two other bases, (+)-11-hydroxyvittatine and hordenine, are also reported from the same plant.
Four groups of Amaryllidaceae alkaloids, namely lycorine-, crinine-, tazettine-, and galanthamine-type, as well as plant extracts of the Amaryllidaceae plants (Pancratium maritimum, Leucojum aestivum, and Narcissus tazetta ssp. tazetta) growing in Turkey were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth by a high-throughput screening method with a 96-well microtiter plate. All four groups of alkaloids exhibited antimalarial activity at different potencies. 6-Hydroxyhaemanthamine, haemanthamine and lycorine were found to be the most potent alkaloids against P. falciparum (T9.96) and galanthamine and tazettine had the least potent activity against P. falciparum (K1).
Plasmodium sporozoites are deposited in the skin of their vertebrate hosts through the bite of an infected female Anopheles mosquito. Most of these parasites find a blood vessel and travel in the peripheral blood circulation until they reach the liver sinusoids. Once there, the sporozoites cross the sinusoidal wall and migrate through several hepatocytes before they infect a final hepatocyte, with the formation of a parasitophorous vacuole, in which the intrahepatic form of the parasite grows and multiplies. During this period, each sporozoite generates thousands of merozoites. As the development of Plasmodium sporozoites inside hepatocytes is an obligatory step before the onset of disease, understanding the parasite's requirements during this period is crucial for the development of any form of early intervention. This Review summarizes our current knowledge on this stage of the Plasmodium life cycle.
Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser(198) has been modeled as bound butyrate.
Continuous natural exposure to Plasmodium transmission by infectious Anopheles mosquitoes leads to a gradual acquisition of immunological competence against malaria. The partial immunity, observed in adolescents and adults living in endemic areas, reduces morbidity and mortality without preventing parasite infection. In experimental animal models, long-lasting sterilizing immunity can be achieved with genetically attenuated Plasmodium liver stages. Can these findings be translated to accomplish sterile protection against natural malaria transmission in the high-risk group, young infants in sub-Saharan Africa?
Phytochemical studies on Galanthus elwesii resulted in the isolation of five alkaloids: incartine, hordenine, hippeastrine, 8-O-demethylhomolycorine and lycorine. The NMR data given previously for incartine were revised and completed by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. In vitro studies on the bioactivity of incartine were carried out.
A structure–activity relationship study was performed with ten 8-aminoquinoline-squaramides compounds active against liver stage malaria parasites, using human hepatoma cells (Huh7) infected by Plasmodium berghei parasites. In addition, their blood-schizontocidal activity was assessed against chloroquine-resistant W2 strain Plasmodium falciparum. Compound 3 was 7.3-fold more potent than the positive control primaquine against liver-stage parasites, illustrating the importance of the squarate moiety to activity.
Two new alkaloids (1, 2) were isolated from the whole plants of Crinum asiaticum var. sinicum together with seven known alkaloids. The structures of the new alkaloids were elucidated by spectroscopic analyses and chemical conversions from known alkaloids. New alkaloid 1 was isolated for the first time as a natural product, although it has been prepared as a synthetic product.
The treatment of many diseases is highly dependent on natural products and natural products can also be used as design templates for future anticancer drugs. Thirteen Amaryllidaceae alkaloids possessing a-crinane, b-crinane, galantamine, lycorine and tazettine-type skeleton have been isolated in our laboratory, and their cytotoxicity against p53-mutated gastrointestinal cancer cells were evaluated. At the same time, healthy small intestine cells were used to determine overall toxicity against noncancerous cells. In this study, we demonstrated that haemanthamine, haemanthidine and lycorine showed strong cytotoxicity against p53-mutated Caco-2 and HT-29 colorectal adenocarcinoma cells as quantified in terms of IC 50 values. We for the first time observed approximately 20 times higher IC 50 values against normal intestine epithelial cells FHs-74 Int after haemanthamine and lycorine treatment when compared with Caco-2 and HT-29 cancer cells. In conclusion, our data indicate that a-C2 bridged haemanthamine may be perspective anticancer drug candidate for further semisynthetic modification and structure-activity relationship study.
Plants from the Amaryllidaceae family have been shown to be a promising source of biologically active natural compounds of which some selected are currently in pre-clinical development. Regardless of interesting pioneer works, little is known about Amaryllidaceae alkaloids that have shown promising anti-cancer activities. The crinane group of the Amaryllidaceae, including haemanthamine and haemanthidine, was amongst the first of these compounds to exhibit an interesting cytotoxic potential against cancer cell lines. However, the mechanism of cytotoxic and anti-proliferative activity is not yet entirely clear. The primary objectives of the current study were to investigate the effects of haemanthamine and haemanthidine on the induction of apoptosis and the cell cycle regulatory pathway in p53-null Jurkat cells. Results indicate that haemanthamine and haemanthidine treatment decreases cell viability and mitochondrial membrane potential, leads to a decline in the percentage of cells in the S phase of the cell cycle, induces apoptosis detected by Annexin V staining and increases caspase activity. Dose dependent apoptosis was cross verified by fluorescence and bright field microscopy through Annexin V/propidium iodine staining and morphological changes which characteristically attend programmed cell death. The apoptotic effect of haemanthamine and haemanthidine on leukemia cells is more pronounced than that of gamma radiation. Contrary to gamma radiation, Jurkat cells do not completely halt the cell cycle 24h upon haemanthamine and haemanthidine exposure. Both Amaryllidaceae alkaloids accumulate cells preferentially at G1 and G2 stages of the cell cycle with increased p16 expression and Chk1 Ser345 phosphorylation. Concerning the pro-apoptotic effect, haemanthidine was more active than haemanthamine in the Jurkat leukemia cell line.
Pancratium littorale Jacq. Collected in Hawaii has beenfound to produce a new phenanthridone, pancratistatin, that significantly inhibits growth of the murine P388 lymphocytic leukaemia; an X-ray crystal structure determination of pancratistatin monomethyl ether (1c) was employed to assign structure (1a) to pancratistatin.
The isolation and characterization of the major crystalline alkaloids of three Crinum species, C. defixum, C. scabrum, and C. latifolium, are reported. A new alkaloid, 5α-hydroxyhomolycorine (1) has been isolated from C. defixum. The latter plant also contains an alkaloid identified as 9-O-demethylhomolycorine which differs in physical properties from that previously reported for this compound. Evidence is provided for the structure of 9-O-demethylhomolycorine by 1H and 13C NMR studies. In the latter, the exploitation of long-range 1H coupling in the 13C spectra of lactones in this series is found to be diagnostically useful in assigning aromatic substitution patterns. A survey of the CD spectra of lactone alkaloids of the benzopyrano[3,4-g]indole system indicates that this technique can provide useful structural information.
Narcissus serotinus belongs to the Amaryllidaceae family, a group well known for an exclusive variety of alkaloids with interesting biological activities. This study was aimed at identifying the alkaloid constituents of N. serotinus collected in the Spanish region of Valencia, using a combination of chromatographic, spectroscopic, and spectrometric methods, including GC-MS and 2D NMR techniques. GC-MS analysis allowed for the direct identification of five known compounds. In addition, the isolation and structure elucidation of six new Amaryllidaceae alkaloids are described.
A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps).
Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Alzheimer's disease (AD) has become one of the deadliest diseases for human beings with special incidence in elderly population. It is a progressive neurodegenerative disease and the most prevalent cause of dementia. The neuropathology of AD has not been fully elucidated yet, however, cholinergic hypothesis is the most accepted theory nowadays, resulting from the cholinergic deficit emerging in the brains of AD patients. Shortage of the neurotransmitters, acetylcholine and butyrylcholine has been demonstrated, and therefore, inhibition of the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that break down acetylcholine and butyrylcholine has become a standard approach for AD treatment. However, cholinesterase inhibitors are only effective in symptomatic treatment and have no ability to impede the disease. The pathogenesis of AD is highly complex and another hypothesis is the formation of amyloid plaques containing beta-amyloid peptide, which causes neurolesions in the brains of AD patients. Beta-amyloid peptide is generated after the sequential cleavage of amyloid precursor protein, especially by the beta- and gamma-secretase in the amyloidogenic pathway. The secretases involved in the processing of amyloid precursor protein are of particular interest and, consequently, the inhibition of secretase enzyme family of protease type has become another desired treatment strategy for AD. On the other hand, medicinal plants are attractive sources for drug research and development as they produce chemically-varying molecules with preferred biological activities. The aim of this article is to review the available data on selected inhibitors from plant secondary metabolites with emphasis on cholinesterase, prolyl endopeptidase, and secretase enzyme families as being the current treatments of AD.
The first obligatory phase of mammalian infection by Plasmodium parasites, the causative agents of malaria, occurs in the liver of the host. This stage of Plasmodium infection bears enormous potential for anti-malarial intervention. Recent technological progress has strongly contributed to overcoming some of the long-standing difficulties in experimentally assessing hepatic infection by Plasmodium. Here, we review appropriate infection models and infection assessment tools, and provide a comprehensive description of recent advances in experimental strategies to investigate the liver stage of malaria. These issues are discussed in the context of current challenges in the field to provide researchers with the technical tools that enable effective experimental approaches to study liver stage malaria.
Twenty seven lycorine derivatives were prepared and evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. The best antiplasmodial activities were achieved with lycorine derivatives that present free hydroxyl groups at C-1 and C-2 or esterified as acetates or isobutyrates. The double bond C-2-C-3 is also important for the activity. Concerning to the antiplasmodial activity of the secolycorines, the higher values were obtained with the replacement of the methylenedioxy moiety by hydroxyl or acetate groups and with methyl substituent attached to the nitrogen atom.
A phytochemical investigation of the bulbs of Brunsvigia radulosa yielded the new alkaloid 1-O-acetylnorpluviine, together with the known structures 1-epideacetylbowdensine, crinamine, crinine, hamayne, lycorine, anhydrolycorin-6-one and sternbergine. All structures were established by spectroscopic evidence. Some of the 13C assignments which were reported for crinamine and hamayne were corrected by means of 2D NMR techniques. In order to provide a further structure for biological testing, crinamine was converted to apohaemanthamine. The alkaloids were tested for activity against two strains of cultured Plasmodium falciparum and for cytotoxicity with BL6 mouse melanoma cells.
A group of serine peptidases, the prolyl oligopeptidase family, cannot hydrolyze peptides containing more than about 30 residues. This group is unrelated to the classical trypsin and subtilisin families, and includes dipeptidyl peptidase IV, acylaminoacyl peptidase and oligopeptidase B, in addition to the prototype prolyl oligopeptidase. The recent crystal structure determination of prolyl oligopeptidase (80 kDa) has shown that the enzyme contains a peptidase domain with an alpha/beta hydrolase fold, and its catalytic triad is covered by the central tunnel of an unusual seven-bladed beta-propeller. This domain operates as a gating filter, excluding large, structured peptides from the active site. The binding mode of substrates and the catalytic mechanism differ from that of the classical serine peptidases in several features. The members of the family are important targets of drug design. Prolyl oligopeptidase is involved in amnesia, depression and blood pressure control, dipeptidyl peptidase IV in type 2 diabetes and oligopeptidase B in trypanosomiasis.
This chapter discusses the chemical and biological aspects of Narcissus alkaloids. Numerous alkaloids have been isolated from Narcissus speciesasaresult of the continuing search for novel alkaloids with pharmacological activity in the Amaryllidaceae family. The alkaloids isolated from this genus, classified in relation to the different skeleton types. The different Narcissus wild species and intersectional hybrids, grouped into subgenera and sections, with their corresponding alkaloids, arranged according to their ring system are listed. The biosynthetic pathways of Narcissus alkaloids includes: (1) enzymatic preparation of the precursors, (2) primary cyclization mechanisms, (3) enzymatic preparation of intermediates, (4) secondary cyclization, diversification, and restructuring. The chapter discusses proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C NMR), and mass spectrometry (MS) for Narcissus alkaloids. A list of the different Narcissus alkaloids, their spectroscopic properties, and literature with the most recent spectroscopic data is given. Several Narcissus extracts shows the following activities: antiviral, prophage induction, antibacterial, antifungal, antimalarial, insecticidal, cytotoxic, antitumor, antimitotic, antiplatelet, hypotensive, emetic, acetylcholine esterase inhibitory, antifertility, antinociceptive, chronotropic, pheromone, plant growth inhibitor, and allelopathic.
Prolyl oligopeptidase (POP) is a serine peptidase which digests small peptide-like hormones, neuroactive peptides, and various cellular factors. Therefore, this peptidase has been implicated in many physiological processes as well as in some psychiatric disorders, most probably through interference in inositol cycle. Intense research has been performed to elucidate, on the one hand, the basic structure, ligand binding, and kinetic properties of POP, and on the other, the pharmacology of its inhibitors. There is fairly strong evidence of in vivo importance of POP on substance P, arginine vasopressin, thyroliberin and gonadoliberin metabolism. However, information about the biological relevance of POP is not yet conclusive. Evidence regarding the physiological role of POP is lacking, which is surprising considering that peptidase inhibitors have been exploited for drug development, some of which are currently in clinical trials as memory enhancers for the aged and in a variety of neurological disorders. Here we review the recent progress on POP research and evaluate the relevance of the peptidase in the metabolism of various neuropeptides. The recognition of novel forms and relatives of POP may improve our understanding of how this family of proteins functions in normal and in neuropathological conditions.
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