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Protein tyrosine phosphatase 1B inhibitory activity of compounds from Justicia spicigera (Acanthaceae)
Abstract
An infusion from the aerial parts of Justicia spicigera Schltdl., an herb commonly used to treat diabetes, inhibited the activity of protein tyrosine phosphatase 1B (PTP1B). Two undescribed compounds, 2-N-(p-coumaroyl)-3H-phenoxazin-3-one, and 3″-O-acetyl-kaempferitrin, along with kaempferitrin, kaempferol 7-O-α-L-rhamnopyranoside, perisbivalvine B and 2,5-dimethoxy-p-benzoquinone were isolated from the active extract. Their structures were elucidated by a combination of spectroscopic and spectrometric methods. The isolates were evaluated for their inhibitory activity against PTP1B; the most active compounds were 2-N-(p-coumaroyl)-3H-phenoxazin-3-one, and perisbivalvine B with IC50 values of 159.1 ± 0.02 μM and 106.6 ± 0.01 μM, respectively. However, perisbivalvine B was unstable. Kinetic analysis of 2-N-(p-coumaroyl)-3H-phenoxazin-3-one and 2,5-dimethoxy-p-benzoquinone (obtained in good amounts) indicated that both compounds behaved as parabolic competitive inhibitors and bind to the enzyme forming complexes with 1:1 and 1:2 stoichiometry. Docking of 2-N-(p-coumaroyl)-3H-phenoxazin-3-one and 2,5-dimethoxy-p-benzoquinone to PTP1B1-400 predicted a good affinity of these compounds for PTP1B catalytic site and demonstrated that the binding of a second ligand is sterically possible. The 1:2 complex was also supported by the second docking analysis, which predicted an important contribution of π-stacking interactions to the stability of these 1:2 complexes. Finally, an UHPLC-MS method was developed and validated to quantify the content of kaempferitrin in the infusion of the plant.
... Compounds of interest, X1 and X2, were identified thanks to their UV-Vis spectra-maximum visible absorption peaks at 492 nm for X1 and 490 nm for X2 at pH 3, which shifted to 586 and 598 respectively at pH 8 [5]-and their pseudo-molecular ions [M+H] + of m/z 404 and 259 for X1 and X2, respectively. Other compounds (flavonols: F1, F2 = kaempferitrin [30] and F3 = kaempferol 3-O-acetyl-rhamnoside 7-O-rhamnoside [31], amino-acid derivative: A1 = justiciamide [32]) identified by their UV-Vis spectra and pseudo-molecular ions were also spotted in the 15 stationary phase-mobile phase combinations to compare their retention in each case. For the three flavonols, pH changes under the tested conditions did not affect their UV-Vis spectrum or their retention. ...
... Compound X2 was identified as a perisbivalvine B (2-amino-8-hydroxy-7-methoxy-3H-phenoxazin-3-one) ( Figure S4), reported in Peristrophe bivalvis [34] and very recently in J. spicigera [31]. The molecular formula of X2 (C 13 Figure S5), corresponding to loss of radical CH3 • and two consecutive losses of CO, consistent with the fragmentation pattern of phenoxazin-3-one derivatives [35,36]. ...
... The relative attributions of the other carbon atoms were then done based on the HMBC correlations, expected weaker for the J2 correlations than for the J3. It is important to note that the attribution of the chemical shifts for the 7-hydro-8-methoxy-phenoxazine-3one derivatives appears to be controversial; for instance, in the previous studies, inconsistent differences are observed for the chemical shifts of carbons C-5a, C-6, C-9, and C-9a for peristrophine [37], perisbivalvine A [34,37], perisbivalvine B [31,34] and amide of the p-coumaroic acid of perisbivalvine B [31]. In our opinion, this can be explained by the lack of solid evidences to determine unambiguously the positions of the hydroxy and methoxy substitutions on the phenoxazin-3-one nucleus. ...
The extensive characterization of the natural dyes involves the purification of their colored compounds for their structural analysis and stability studies. As most natural compounds being ionizable, herein is presented the optimization of an easy and affordable preparative bidimensional offline reversed‐phase high‐performance liquid chromatography purification based on mobile phase pH change. At the analytical scale, several combinations of stationary phases and mobile phases at different pH values were investigated first. The orthogonality between the dimensions was quantitatively evaluated using the nearest‐neighbor distance approach. The optimized separation method was transferred to the preparative scale for the successful isolation of two colored compounds from Justicia spicigera, a traditional dye plant from Central America. They were identified as perisbivalvine B (2‐amino‐8‐hydroxy‐7‐methoxy‐3H‐phenoxazin‐3‐one) and one of its derivatives, also found in another tinctorial plant species, Peristrophe bivalvis growing in Asia.
... uk/entry/P18031 30 . This structure was subjected to a molecular dynamics simulation for 50 ns to find the most stable conformation of the unstructured region (301-400) 31 . The structures of the ligands were constructed and minimised using AVOGRADRO software 32 . ...
In the present work, we studied the inhibitory and kinetic implications of classical PTP1B inhibitors (chlorogenic acid, ursolic acid, suramin) using three enzyme constructs (hPTP1B1-285, hPTP1B1-321, and hPTP1B1-400). The results indicate that the unstructured region of PTP1B (300-400 amino acids) is very important both to obtain optimal inhibitory results and propose classical inhibition mechanisms (competitive or non-competitive) through kinetic studies. The IC50 calculated for ursolic acid and suramin using hPTP1B1-400 are around four and three times lower to the short form of the enzyme, the complete form of PTP1B, the one found in the cytosol (in vivo). On the other hand, we highlight the studies of enzymatic kinetics using the hPTP1B1-400 to know the type of enzymatic inhibition and to be able to direct docking studies, where the unstructured region of the enzyme can be one more option for binding compounds with inhibitory activity.
Levodopa (LD) is the first discovered and the most promising and effective medication for Parkinson’s disease (PD). As the first identified natural source of LD, Vicia faba L. (broad beans), especially its sprouts, has been confirmed to contain many other potential bioactive compounds that could also be therapeutic for PD. In this study, the bioactive components obtained from broad bean sprout extraction (BSE) that could be beneficial for PD treatment were screened, and the related mechanisms were explored. Solvent extraction combined with column chromatography was used to isolate bioactive fractions and monomer compounds, while UPLC-ESI-MS/MS, HRESI-MS and (¹H, ¹³C) NMR were employed for compound identification. Network pharmacology techniques were applied to screen for potential mechanisms. A total of 52 compounds were identified in a 50% MeOH extract of broad bean sprouts. Moreover, twelve compounds were isolated and identified from ethyl acetate and n-butanol portions, including caffeic acid (1), trans-3-indoleacrylic acid (2), p-coumaric acid (3), protocatechualdehyde (4), isovitexin (5), isoquercetin (6), grosvenorine (7), kaempferol-3-O-rutinoside (8), isoschaftoside (9), narcissin (10), kaempferitrin (11) and trigonelline HCl (12). Compounds 2, 4, 7, 8 and 12 were isolated from Vicia faba L. for the first time. The potential mechanisms were determined by analyzing 557 drug targets, 2334 disease targets and 199 intersections between them using a protein–protein interaction (PPI) network, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) enrichment. Further in vitro experiments confirmed that caffeic acid (compound 1) and p-coumaric acid (compound 3) have neuroprotective effects in 6-hydroxydopamine-treated SH-SY5Y cells and lipopolysaccharide-treated PC-12 cells through anti-inflammatory and antioxidant mechanisms. In conclusion, this study explored effective components in broad bean sprouts and performed in vitro evaluations.
The genus Justicia has more than 600 species distributed in both hemispheres, in the tropics and temperate regions, and it is used in the treatment of numerous pathologies. This study presents a review of the biological activities of plant extracts and isolated chemical constituents of Justicia (ACANTHACEAE), identified in the period from May 2011 to August 2022. We analyzed over 176 articles with various biological activities and chemical compound descriptions present in the 29 species of Justicia. These have a variety of applications, such as antioxidant and antimicrobial, with alkaloids and flavonoids (e.g., naringenin) the most frequently identified secondary metabolites. The most observed species were Justicia gendarussa Burm., Justicia procumbens L., Justicia adhatoda L., Justicia spicigera Schltdl, and Justicia pectoralis Jacq. The frontier molecular orbitals carried out using density functional theory (M062X and basis set 6-311++G(d,p) indicate reactive sites for naringenin compound and a chemical reaction on phytomedicine activity. The energy gap (206.99 kcal/mol) and dimer solid state packing point to chemical stability. Due to the wide variety of pharmacological uses of these species, this review points toward the development of new phytomedicines.
Diabetes mellitus (DM) represents a complex and multifactorial disease that causes metabolic disorders with acute and long-term serious complications. The onset of DM, with over 90% of cases of diabetes classified as type 2, implies several metabolic dysfunctions leading to consider DM a worldwide health problem. In this frame, protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) are two emerging targets involved in the development of type 2 diabetes mellitus (T2DM) and its chronic complications. Herein, we employed a marine-derived dual type inhibitor of these enzymes, phosphoeleganin, as chemical starting point to perform a fragment-based process in search for new inhibitors. Phosphoeleganin was both disassembled by its oxidative cleavage and used as model structure for the synthesis of a small library of functionalized derivatives as rationally designed analogues. Pharmacological screening supported by in silico docking analysis outlined the mechanism of action against PTP1B exerted by a phosphorylated fragment and a synthetic simplified analogue, which represent the most potent inhibitors in the library.
This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.
An extract from a PDB static culture of Malbranchea dendritica exhibited α-glucosidase and PTP-1B inhibitory activities. Fractionation of the active extract led to the isolation of gymnoascolide A (1), a γ-butenolide, and xanthones sydowinin A (2), sydowinin B (3), and AGI-B4 (4), as well as orcinol (5). Compound 1 exhibited important inhibitory activity against yeast α-glucosidase (IC50 = 0.556 ± 0.009 mM) in comparison to acarbose (IC50 = 0.403 ± 0.010 mM). Kinetic analysis revealed that 1 is a mixed-type inhibitor. Furthermore, compound 1 significantly reduced the postprandial peak in mice during a sucrose tolerance test at the doses of 5.16 and 10 mg/kg. Compound 1 was reduced with Pd/C to yield a mixture of enantiomers 1a and 1b; the mixture showed similar activity against α-glucosidase (IC50 = 0.396 ± 0.003 mM) and kinetic behavior as the parent compound but might possess better drug-likeness properties according to SwissADME and Osiris Property Explorer tools. Docking analysis with yeast α-glucosidase (pdb: 3A4A) and the C-terminal subunit of human maltase-glucoamylase (pdb: 3TOP) predicted that 1, 1a, and 1b bind to an allosteric site of the enzymes. Compounds 1–5 were evaluated against PTP-1B, but only xanthone 3 moderately inhibited in a noncompetitive fashion the enzyme with an IC50 of 0.081 ± 0.004 mM. This result was consistent with that of docking analysis, which revealed that 3 might bind to an allosteric site of the enzyme. From the inactive barley-based semisolid culture of M. dendritica, the natural pigment erythroglaucin (6) and the nucleosides deoxyadenosine (7), adenosine (8), thymidine (9), and uridine (10) were also isolated and identified.
Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1, 2, 3–4, the structures of around 100,000 unique proteins have been determined⁵, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’⁸—has been an important open research problem for more than 50 years⁹. Despite recent progress10, 11, 12, 13–14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)¹⁵, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.
Background
Papaveraceae Argemone mexicana L., Burseraceae Bursera simaruba (L.) Sarg., Acanthaceae Justicia spicigera Schltdl. and Selaginellaceae Selaginella lepidophylla (Hook. & Grev.) Spring., have been used in Mexican traditional medicine to treat hypertension. The objective of this study was to further characterize the cardiovascular effects of the methanol extracts of such plants.
Methods
The medicinal plants were collected and taxonomically identified; the methanol extract of each explored plant were administrated to conscious and unconscious male Wistar rats with and without glucose-induced hypertension. The blood pressure (BP) and heart rate (HR) were evaluated before and after the extract administration. Vascular reactivity experiments were conducted in rat aortic rings obtained from rats with and without sugar-induced hypertension, a model widely used to study such effects with cardiovascular agents.
Results
After oral administration in normotensive conscious rats all tested extracts decreased the HR, such effect was only observed in hypertensive conscious rats after the administration of B. simaruba; only A. mexicana and B. simaruba decreased the BP after oral administration. All extracts administrated by intravenous injection diminished the mean arterial pressure. Dose-response curves to cumulative concentrations of all the extracts promote vascular relaxation in precontracted aortas from rats with and without sugar-induced hypertension.
Conclusions
The present study indicated that B. simaruba is worthy of further investigation as a potential phytotherapeutic agent for treating hypertension.
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Justicia spicigera is a native plant from Mexico used since prehispanic times to treat dysentery. The aim of this research was to evaluate the effect of ethanol extract (EE) and its hexanic fraction (HEE) on bacteria causing dysentery, as well as on Staphylococcus aureus and the yeast Candida albicans. The minimal inhibitory concentration (MIC) was determined by resazurin assay. The EE inhibited the growth of Shigella flexneri, Salmonella typhi, Salmonella typhimurium, Escherichia coli and Staphylococcus aureus MIC ≤ 2.5 mg/mL. The HEE inhibited bacterial growth MIC ≤ 1.25 mg/mL. This fraction also inhibited Candida albicans with MIC = 0.25 mg/mL. These results support the empirical use of Justicia specigera to dysentery treatment. The volatile compounds of the HEE, a fragrant yellow oil, were analyzed by gas chromatography-mass spectrometry and identified by the NIST library: 3-pentenal,4-methyl; butanoic acid, 2-hydroxi-2-methyl-,methyl ester; ethanone, 1-(3-ethyloxiranyl)-; 1-butanol,4-(1-methylethoxy)-; 2-hydroxy-2-methylbutyric acid; 3-butene-1,2-diol, 1-(2-furanyl)-; 2-hexenoic acid ethyl ester; 3-thiopheneacetic acid; 1,2-benzendicarboxilic acid, mono (2-ethylhexyl) ester; benzene, 1,1'-(-1-phenyl-1,2-ethenediyl) bis[4-methoxy]. None of these compounds have been reported previously from Justicia spicigera.
The cardiovascular disorder of hypertension is one of the main non-communicable diseases worldwide, and
is responsible for over 80% of the deaths in low- and middle-income countries. Justicia spicigera (muicle) is a
plant used in Mexican traditional medicine for the treatment of various disorders, including hypertension.
The principle aim of this work was to evaluate the effects on blood pressure of different extracts taken from
the aerial parts of the muicle plant Justicia spicigera (Acanthaceae). To the best of our knowledge there are
no such previous reports. For the purpose of this study, the extracts were applied in hypertensive L-NAME
Wistar rats. The results show that hexane and methanol extracts did not lower blood pressure and the
aqueous extract only decreased the diastolic blood pressure (from 163/148 ± 6.65/6.64 mmHg to 156/128 ±
11.8/4.51 mmHg) in the hypertensive rats, but not in the normotensive animals. However, the chloroform
extract lowered the arterial blood pressure (180/164 ± 1.7/3.2 mmHg) to values similar to those of the normotensive
rats (149/133 ± 4.0/3.7 mmHg). The extracts had no effect on the control animals and the vehicles did
not modify arterial blood pressure in any of the animals. Finally, the chloroform extract of aerial parts of J.
spicigera was further analyzed by high performance liquid chromatography (HPLC) to identify and quantify
major bioactive flavonoid compounds profile. As revealed by the results, the chloroform extract yielded three
major flavonoid compounds, identified as hesperidin, naringenin and kaempferol, metabolites that could be
responsible of antihypertensive effects of J. spicigera.
The cardiovascular disorder of hypertension is one of the main non-communicable diseases worldwide, and is responsible for over 80% of the deaths in low- and middle-income countries. Justicia spicigera (muicle) is a plant used in Mexican traditional medicine for the treatment of various disorders, including hypertension. The principle aim of this work was to evaluate the effects on blood pressure of different extracts taken from
the aerial parts of the muicle plant Justicia spicigera (Acanthaceae). To the best of our knowledge there are
no such previous reports. For the purpose of this study, the extracts were applied in hypertensive L-NAME
Wistar rats. The results show that hexane and methanol extracts did not lower blood pressure and the
aqueous extract only decreased the diastolic blood pressure (from 163/148 ± 6.65/6.64 mmHg to 156/128 ± 11.8/4.51 mmHg) in the hypertensive rats, but not in the normotensive animals. However, the chloroform
extract lowered the arterial blood pressure (180/164 ± 1.7/3.2 mmHg) to values similar to those of the normotensive rats (149/133 ± 4.0/3.7 mmHg). The extracts had no effect on the control animals and the vehicles did not modify arterial blood pressure in any of the animals. Finally, the chloroform extract of aerial parts of J. spicigera was further analyzed by high performance liquid chromatography (HPLC) to identify and quantify major bioactive flavonoid compounds profile. As revealed by the results, the chloroform extract yielded three major flavonoid compounds, identified as hesperidin, naringenin and kaempferol, metabolites that could be responsible of antihypertensive effects of J. spicigera.
Chemical investigation of the marine Streptomyces sp. Eg25 led to the isolation of one new natural 2-aminophenoxazin-3-one-8-carboxylic acid methyl ester named maroxazinone (1) as well as the known compounds elloxazinone A (2), exfoliazone (3), carboxyexfoliazone (4), elloxazinone B (5) and venezueline D (6). The chemical structures of the isolated compounds were deduced from extensive studies of NMR ((1)H and (13)C NMR, (1)H-(1)H COSY, HMQC and HMBC) and mass spectra. The cytotoxic activities of the new maroxazinone (1) and venezueline D (6) against breast carcinoma cell line (MCF7), liver carcinoma cell line (HEPG2) and colon carcinoma cell line (HCT116) were investigated.
The in vitro. activity of 10 methanol extracts prepared from native plants collected in the Yucatan Peninsula [Byrsonima crassifolia. (L.) Kunth, Cupania dentata. DC., Diphysa carthagenensis. Jacq., Dorstenia contrajerva. L., Gliricidia sepium. (Jacq.) Kunth ex Walp., Justicia spicigera. Schldl., Pluchea odorata. (L.) Cass., Spigelia anthelmia. L., Tridax procumbens. L., and Triumfetta semitriloba. Jacq.] was evaluated against Giardia lamblia. trophozoites. All the extracts showed activity against G. lamblia. trophozoites. T. procumbens. was most active, with an IC50 of 6.34 µg/ml, followed by C. dentata., 7.59 µg/ml, D. carthagenensis., 11.53 µg/ml, and B. crassifolia., 15.55 µg/ml.
Background
The Avogadro project has developed an advanced molecule editor and visualizer designed for cross-platform use in computational chemistry, molecular modeling, bioinformatics, materials science, and related areas. It offers flexible, high quality rendering, and a powerful plugin architecture. Typical uses include building molecular structures, formatting input files, and analyzing output of a wide variety of computational chemistry packages. By using the CML file format as its native document type, Avogadro seeks to enhance the semantic accessibility of chemical data types.
Results
The work presented here details the Avogadro library, which is a framework providing a code library and application programming interface (API) with three-dimensional visualization capabilities; and has direct applications to research and education in the fields of chemistry, physics, materials science, and biology. The Avogadro application provides a rich graphical interface using dynamically loaded plugins through the library itself. The application and library can each be extended by implementing a plugin module in C++ or Python to explore different visualization techniques, build/manipulate molecular structures, and interact with other programs. We describe some example extensions, one which uses a genetic algorithm to find stable crystal structures, and one which interfaces with the PackMol program to create packed, solvated structures for molecular dynamics simulations. The 1.0 release series of Avogadro is the main focus of the results discussed here.
Conclusions
Avogadro offers a semantic chemical builder and platform for visualization and analysis. For users, it offers an easy-to-use builder, integrated support for downloading from common databases such as PubChem and the Protein Data Bank, extracting chemical data from a wide variety of formats, including computational chemistry output, and native, semantic support for the CML file format. For developers, it can be easily extended via a powerful plugin mechanism to support new features in organic chemistry, inorganic complexes, drug design, materials, biomolecules, and simulations. Avogadro is freely available under an open-source license from
http://avogadro.openmolecules.net.
Peristrophe bivalvis (L.) Merr. (Acanthaceae) is a wild growing and cultivated plant used for dyeing of foods by the ethnic minorities of Vietnam. The major component of the colour aqueous extract (CAE) of its leaves was identified as peristrophine by spectral analysis, especially the 2D NMR spectra (HSQC, HMBC and NOESY). Considering the widespread utilisation of the decoction of this plant for food dyeing, we evaluated the acute oral toxicity of the CAE. Based on the results in an acute toxicity study in mice, the LD(50) value of the CAE was determined as 9100 ± 290 mg kg(-1) body weight. Additionally, in vitro cytotoxic assay showed an inhibition of peristrophine against Hepatocellular carcinoma (HepG2, IC(50)3.90 µg mL(-1)). CAE and peristrophine (1) have also been tested for their ability to affect the cell number of the OCI acute myeloid leukaemia cell line. CAE and peristrophine significantly decreased the OCI cell number at different concentrations and times of treatment.
The antimicrobial effects of the Mexican medicinal plants Guazuma ulmifolia, Justicia spicigera, Opuntia joconostle, O. leucotricha, Parkinsonia aculeata, Phoradendron longifolium, P. serotinum, Psittacanthus calyculatus, Tecoma stans and Teucrium cubense were tested against several human multi-drug resistant pathogens, including three Gram (+) and five Gram (-) bacterial species and three fungal species using the disk-diffusion assay. The cytotoxicity of plant extracts on human cancer cell lines and human normal non-cancerous cells was also evaluated using the MTT assay. Phoradendron longifolium, Teucrium cubense, Opuntia joconostle, Tecoma stans and Guazuma ulmifolia showed potent antimicrobial effects against at least one multidrug-resistant microorganism (inhibition zone > 15 mm). Only Justicia spicigera and Phoradendron serotinum extracts exerted active cytotoxic effects on human breast cancer cells (IC50 < or = 30 microg/mL). The results showed that Guazuma ulmifolia produced potent antimicrobial effects against Candida albicans and Acinetobacter lwoffii, whereas Justicia spicigera and Phoradendron serotinum exerted the highest toxic effects on MCF-7 and HeLa, respectively, which are human cancer cell lines. These three plant species may be important sources of antimicrobial and cytotoxic agents.
The aim of this review was to discuss an overview of type 2 diabetes; biology of PTP1B; role of PTP1B in metabolic disorders; and recent updates in the development of PTP1B inhibitors reported in literature since 1994. In this study, extensive literature search was carried out on PTP1B inhibitors of natural as well as synthetic origin in various scientific databases and research articles related to discovery of PTP1B inhibitors were selected for this study. Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for several human diseases including type 2 diabetes, obesity and cancer because of its seminal part as a negative modulator in both insulin and leptin signaling pathways. A large number of molecules of broad chemical diversity were reported as potent and selective PTP1B inhibitors over other protein tyrosine phosphatases. Several of these molecules have shown their potential in the treatment of various human diseases including type 2 diabetes, obesity, inflammation and cancer in various animal models. But only a very limited number of PTP1B inhibitors (including ertiprotafib, trodusquemine and JTT-551) has entered clinical trials and are finally withdrawn owing to their unsatisfactory effectiveness and undesirable adverse effects. Consequently, it is still highly imperative and of great importance to develop potent, highly selective and safe PTP1B inhibitors.
Characterisation of vegetal colourants in manuscripts is still a challenging task. Their identification using non-invasive techniques - since sampling is rarely possible - is valid only if there is evidence that the recorded signals are generated by compounds specific to the plant species. Otherwise, more extensive chemical characterisations are required to relate the non-invasive technique signals to the chemical composition of the dye extract and thus avoid misidentification. The case study of a traditional Mesoamerican dye found in the Codex Borbonicus is reported herein. The non-invasive identification of the colourant plant source and chemical characterisation of the coloured molecules were carried out through a multi-analytical technique approach. In situ Raman and UV-Vis emission fluorescence signals suggested the use of Justicia spicigera leaves to produce the brown paint layers of the manuscript. Analysis of the plant extract by liquid chromatography revealed that two compounds are mostly responsible for the colour, and these compounds were successfully isolated. Both contribute to the Raman spectra while only one of them is mainly responsible for the fluorescence recorded on Codex Borbonicus.
From solid rice-based cultures of Malbranchea albolutea, three undescribed ardeemins and sartoryglabrins analogs were discovered and named alboluteins A-C. 1H-Indole-3-carbaldehyde, and anthranilic acid were also isolated. 1D and 2D-NMR techniques, as well as DFT-calculated chemical shifts, allowed characterizing alboluteins A-C. Testing these compounds against PTP1B indicated their inhibitory activity with IC50's ranging from 19 to 129 μM (ursolic acid IC50 = 29.8 μM, positive control). Kinetic analysis revealed that albolutein C behaved as a non-competitive inhibitor. Docking studies of alboluteins A-C into the crystal structure of PTP1B (PDB ID: 1T49) predicted that all compounds prefer to bind at the allosteric site of the enzyme, with Ki values of 2.02 × 10⁻⁴, 1.31 × 10⁻⁴, and 2.67 × 10⁻⁴ mM, respectively. Molecular dynamic studies indicated that the active compounds remained tied to the enzyme with good binding energy.
A critical biological event that contributes to the appearance and progress of cancer and diabetes is the reversible phosphorylation of proteins, a process controlled by protein tyrosine-kinases (PTKs) and protein tyrosine-phosphatases (PTPs). Within the PTPs, PTP1B has gained significant interest since it is a validated target in drug discovery. Indeed, several PTP1B inhibitors have been developed, from both, synthesis and natural products. However, none have been approved by the FDA, due to their poor selectivity and/or pharmacokinetic properties. One of the most significant challenges to the discovery of PTP1B inhibitors (in vitro or in silico) is the use of truncated structures (PTP1B1-300), missing valuable information about the mechanisms of inhibition, and selectivity of ligands. The present study describes the biochemical characterization of a full-length PTP1B (hPTP1B1-400), as well as the description of phenalenones 1-4 and ursolic acid (5) as allosteric modulators. Compounds 1-5 showed inhibitory potential on hPTP1B1-400, with IC50 values ranging from 12.7 to 82.1 µM. Kinetic studies showed that 1 and 5 behave as mixed and non-competitive inhibitors, respectively. Circular dichroism experiments confirmed that 1 and 5 induced conformational changes to hPTP1B1-400. Further insights into the structure of hPTP1B1-400 were obtained from a homology model, which pointed out that the C-terminus (residues 301-400) is highly disordered. Molecular docking with the homologated model suggested that compounds 1 and 3-5 bind to the C-terminal domain, likely inducing conformational changes on the protein. Docking positions of compounds 1, 4, and 5 were refined with molecular dynamics simulations. Importantly, these simulations confirmed the high flexibility of the C-terminus of hPTP1B1-400, as well as the changes to its rigidity when bound to 1, 4, and 5.
Justicia spicigera is a plant used in traditional Mexican medicine to treat various diseases such as heart diseases and to improve blood circulation, with little scientific evidence. Therefore, this study evaluated the effect of the leaves of the plant and of kaempferitrin (main active ingredient), on biochemical, physiological, and inflammation markers related to obesity induced by a high-fat diet in male Wistar rats for eight weeks. The results indicated that J. spicigera powder has the ability to significantly decrease (p ≤ 0.05) the percentage of accumulated fat, and consequently, weight gain, as well as serum triglyceride concentrations. In addition, both J. spicigera powder and kaempferitrin generated transcriptional adaptations by negatively modulating the expression of pro-inflammatory genes such as Tlr4, Tnf-α, Nlrp3, Caspase-1, Il-18, Il-1β, Srebp-1c, Ppar-γ and Ucp2 and overexpressing Ppar-α.
During a search for new α-glucosidase and protein tyrosine phosphatase 1B inhibitors from fungal sources, eight new secondary metabolites, including two anthranilic acid-derived peptides (1 and 2), four glycosylated anthraquinones (3-6), 4-isoprenylravenelin (7), and a dimer of 5,8-dihydroxy-4-methoxy-α-tetralone (8), along with four known compounds (9-12), were isolated from solid rice-based cultures of Malbranchea circinata. The structural elucidation of these metabolites was performed using 1D and 2D NMR techniques and DFT-calculated chemical shifts. Compounds 1-3, 9, and 10 showed inhibitory activity to yeast α-glucosidase (αGHY), with IC50 values ranging from 57.4 to 261.3 μM (IC50 acarbose = 585.8 μM). The effect of 10 (10.0 mg/kg) was corroborated in vivo using a sucrose tolerance test in normoglucemic mice. The most active compounds against PTP-1B were 8-10, with IC50 values from 10.9 to 15.3 μM (IC50 ursolic acid = 27.8 μM). Docking analysis of the active compounds into the crystal structures of αGHY and PTP-1B predicted that all compounds bind to the catalytic domains of the enzymes. Together, these results showed that M. circinata is a potential source of antidiabetic drug leads.
Background
Protein tyrosine phosphatases are enzymes which help in signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development significant progress has been made over the last 10 years, few compounds has reached in early-stage clinical trials whereas later stage trials or registration yet none have progressed. Many researchers are investigating different ways to improve the pharmacological properties of PTP1B inhibitors.
Objective
In the present review, authors have summarized various aspects related to involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus.
Conclusion
There are still certain challenges for selection of PTP1B as a drug target. Therefore continuous future efforts are needed to explore this target for development of PTP inhibitors to treat the prevailing diseases associated with it.
Justicia spicigera Schltdl. (Acanthaceae) is used for treatment of gastrointestinal illnesses therapy in traditional medicine. The objective of this study was to give evidence of the antinociceptive and spasmolytic effects of the J. spicigera ethanol extract (JS EtOH) using in in vivo and/or in vitro assays. The JS EtOH exerted regulatory effect on the motility and a partial relaxing response on the intestinal tissue. Furthermore, a significant abdominal antinociceptive response was obtained in mice, which was totally abolished in the presence of 5-HT1A receptor antagonist (WAY100635, 0.1 mg/kg, s.c.) and partially by blocking opioid receptors (NX, 1 mg/kg, i.p.), whereas the inhibition of the NO synthesis (L-NAME, 30 mg/kg, i.p.) facilitated antinociception of this extract. Kaempferitrin was isolated and identified as major secondary metabolite. These results support the analgesic and spasmolytic-like activity of J. spicigera aerial parts involving inhibitory neurotransmission reinforcing the potential of this medicinal plant for alleviating pain.
Background: Justicia spicigera is widely used in the Mexican traditional medicine for the treatment of inflammation. Objectives: The purpose of this study was to investigate the anti-inflammatory effect of procumbenoside B (PB) from J. spicigera on pro-inflammatory mediators. Materials and Methods: Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and Zebrafish model were used to assess the potential anti-inflammatory effects of PB; its structure was elucidated on the basis of spectroscopic data. The production of inflammatory mediators such as interferon-β, prostaglandin E2, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB) p65, interleukin-6 (IL-6), IL-1β, IL-12, cyclooxygenase (COX-2), tumor necrosis factor-α, and anti-inflammatory IL-10 was measured using enzyme-linked immunosorbent assay. NO production was measured using Griess reagent. Results: In LPS-induced-inflammatory response in RAW264.7 macrophage cells, PB strongly inhibited secretion of all pro-inflammatory mediators test and increased the production of IL-10 and blockade of NF-κB. In addition, PB suppressed LPS-stimulated nitric oxide and reactive oxygen species generation in a zebrafish model. Conclusion: These results indicated that the anti-inflammatory effects of PB may be attributed to the downregulation of iNOS and COX-2 through the suppression of NF-κB signaling pathway in RAW264.7 macrophages. Abbreviations used: 4-Amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM-DA), Cyclooxygenase-2 (COX-2), 2,7-dichlorofluorescein (DCH-DA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Dimethylsulphoxide (DMSO), Dulbecco's modified eagle's medium (DMEM), Fetal bovine serum (FBS), Granulocyte-macrophage colony-stimulating factor (GM-CSF), Interferon-β (IFN β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1B (IL-1b), Layer chromatography (TLC), Lipopolysaccharide (LPS), Matrix metalloproteinases-3 (MMP-3), Matrix metalloproteinases-13 (MMP-13), Nitric oxide (NO), Nitric oxide synthase (iNOS), Nuclear factor-kappa B (NF-βB), Prostaglandin E2 (PGE2), Reactive oxygen species (ROS), Tumor necrosis factor-β (TNF-β). © 2018 Pharmacognosy Research | Published by Wolters Kluwer - Medknow.
Background: Chemotherapy of schistosomiasis by certain drugs is impractical due to the resistance of Schistosoma larvae to schistosomiasis drugs after long treatment period. The aim of this work is to monitor Schistosoma mansoni infection on mice livers after treatment with the ethanolic extract of Justicia spicigera areal parts and the herbal antishistosomal drug (Mirazid); the oleo-resin extract from Myrrh of Commiphora molmol tree. Methods: Liver function enzymes; Aspartate Aminotransferase (AST); Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Gamma Glutamyl Trans-Peptidase (GGT) and serum total protein content were estimated. Oxidative stress markers; Malondialdehyde (MDA), Glutathione (GSH) and Super Oxide Dismutase (SOD) were also evaluated. Parasitological and histopathological studies through numbers of worm burden and liver pathology pattern were done. Results: The results showed obvious decreases in AST, ALT, ALP, GGT, total protein, MDA and SOD after treatment with plant extract or the selected drug, while GSH recorded significant increase after treatment. A noticeable decrease in worm count and an improvement in histopathological picture of the infected mice liver were detected. Conclusion: The ethanolic extract of Justicia spicigera areal parts recorded antioxidants and antischis-tosomal effects. Further work is needed to validate its safety and for considering it as anti-schisotosomal drug.
Since PTP1B enzyme was discovered in 1988, it has captured the research community’s attention. This landmark discovery has stimulated numerous research studies on a variety of human diseases, including cancer, inflammation, and diabetes. Tremendous progress has been made in finding PTP1B inhibitors and exploring PTP1B regulatory mechanisms. This review investigates for the natural PTP1B inhibitors, and focuses on the common characteristics of the discovered structures and structure–activity relationships. To facilitate understanding, all the natural compounds are here divided into five different classes (fatty acids, phenolics, terpenoids, steroids, and alkaloids), according to their skeletons. These PTP1B inhibitors of scaffold structures could serve as a theoretical basis for new concept drug discovery and design.
Justicia spicigera Schltdl. (Acanthaceae) is a plant used in traditional Mexican medicine to treat several types of cancer. Some studies reported cytotoxic effects of J. spicigera extracts on cancer cell lines, but that the androgen-independent DU-145 prostate cancer cell line resists its cytotoxic action. The aim of the present study was to investigate whether an hydroalcoholic J. spicigera extract (HJsE) exerts antiproliferative and cytotoxic effects on the androgen-dependent stage of prostate cancer, thus contributing to the scientific validation of this plant for prostate cancer treatment. LNCaP cells were treated with HJsE (62.5-4000μg/ml) for 24-72h. HJsE reduced the proliferation of LNCaP cells by 62%±1.7% (IC50 =3026±421μg/ml) without affecting cell viability, assessed by both MTT assay and cell counting based on Trypan blue exclusion assay. Ki-67 immunostaining revealed that HJsE (4000μg/ml) increased the percentage of cells in the G0 phase (Ki-67-negative; 5.26%±0.82%, p< 0.001) and interphase (late G1/S/G2; 4.37%±0.82%, p< 0.01), decreased the percentage of cells in the early G1 phase (1.76%±0.82%, p <0.001), and decreased the percentage of cells that progressed to mitosis (7.87%±0.82%, p <0.001). HJsE had low cytotoxicity in LNCaP cells (IC50 >4000μg/ml). These results indicate that HJsE affects the proliferation of LNCaP cells through a cytostatic mechanism rather than a cytotoxic mechanism, preventing the progression to mitosis in the cell-cycle. The cytostatic potential of HJsE should be explored in other models of prostate cancer to demonstrate its utility as an alternative strategy for prostate cancer treatment.
Preclinical Research
The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine‐induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180–186, 2016. © 2016 Wiley Periodicals, Inc.
Computational docking can be used to predict bound conformations and free energies of binding for small-molecule ligands to macromolecular targets. Docking is widely used for the study of biomolecular interactions and mechanisms, and it is applied to structure-based drug design. The methods are fast enough to allow virtual screening of ligand libraries containing tens of thousands of compounds. This protocol covers the docking and virtual screening methods provided by the AutoDock suite of programs, including a basic docking of a drug molecule with an anticancer target, a virtual screen of this target with a small ligand library, docking with selective receptor flexibility, active site prediction and docking with explicit hydration. The entire protocol will require ∼5 h.
Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity.
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (FITS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements. (C) 2012 Published by Elsevier B.V.
We present an implementation of explicit solvent all atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA-enabled GPUs. First released publicly in April 2010 as part of version 11 of the AMBER MD package and further improved and optimized over the last two years, this implementation supports the three most widely used statistical mechanical ensembles (NVE, NVT, and NPT), uses particle mesh Ewald (PME) for the long-range electrostatics, and runs entirely on CUDA-enabled NVIDIA graphics processing units (GPUs), providing results that are statistically indistinguishable from the traditional CPU version of the software and with performance that exceeds that achievable by the CPU version of AMBER software running on all conventional CPU-based clusters and supercomputers. We briefly discuss three different precision models developed specifically for this work (SPDP, SPFP, and DPDP) and highlight the technical details of the approach as it extends beyond previously reported work [Götz et al., J. Chem. Theory Comput. 2012, DOI: 10.1021/ct200909j; Le Grand et al., Comp. Phys. Comm. 2013, DOI: 10.1016/j.cpc.2012.09.022].We highlight the substantial improvements in performance that are seen over traditional CPU-only machines and provide validation of our implementation and precision models. We also provide evidence supporting our decision to deprecate the previously described fully single precision (SPSP) model from the latest release of the AMBER software package.
We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the analysis and processing of time series of three-dimensional atomic positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange molecular dynamics), image with periodic boundary conditions, create average structures, strip subsets of the system, and perform calculations such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ.
Highlights
► Chemical constituents of red and purple forms of P. bivalvis (L.) Merr. are reported. ► Peristrophe bivalvis is reported as a new source for natural phenoxazine alkaloids. ► The novel perisbivalvine A was found in purple forms of P. bivalvis.
ETHNOPHARMACOLOGICAL IMPORTANCE: Justicia spicigera is a plant species used for the Teenak (Huesteca Potosina) and Mayan (Yucatan peninsula) indigenous for the empirical treatment of diabetes, infections and as stimulant.
To evaluate the cytotoxicity, antioxidant and antidiabetic properties of J. spicigera.
The effects of ethanolic extracts of J. spicigera (JSE) on the glucose uptake in insulin-sensitive and insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes was evaluated. The antioxidant activities of the extract of JSE was determined by ABTS and DPPH methods. Additionally, it was evaluated the antidiabetic properties of JSE on T2DM model.
JSE stimulated 2-NBDG uptake by insulin-sensitive and insulin-resistant human and murine adipocytes in a concentration-dependent manner with higher potency than rosiglitazone 1mM. JSE showed antioxidant effects in vitro and induced glucose lowering effects in normoglycemic and STZ-induced diabetic rats.
The antidiabetic effects of administration of J. spicigera are related to the stimulation of glucose uptake in both insulin-sensitive and insulin-resistant murine and human adipocytes and this evidence justify its empirical use in Traditional Medicine. In addition, J. spicigera exerts glucose lowering effects in normoglycemic and STZ-induced diabetic rats.
Chemical profiling of a Streptomyces griseus strain isolated from an old building with moisture damage led to the discovery of two novel phenoxazinones, chandrananimycin D and pitucamycin , along with the known grixazone B. Pitucamycin represents an unprecedented hybrid molecule composed of a phenoxazinone and an enaminomycin-like epoxyquinone moiety.
This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
Literature data on compounds both well- and poorly-absorbed in humans were used to build a statistical pattern recognition model of passive intestinal absorption. Robust outlier detection was utilized to analyze the well-absorbed compounds, some of which were intermingled with the poorly-absorbed compounds in the model space. Outliers were identified as being actively transported. The descriptors chosen for inclusion in the model were PSA and AlogP98, based on consideration of the physical processes involved in membrane permeability and the interrelationships and redundancies between available descriptors. These descriptors are quite straightforward for a medicinal chemist to interpret, enhancing the utility of the model. Molecular weight, while often used in passive absorption models, was shown to be superfluous, as it is already a component of both PSA and AlogP98. Extensive validation of the model on hundreds of known orally delivered drugs, "drug-like" molecules, and Pharmacopeia, Inc. compounds, which had been assayed for Caco-2 cell permeability, demonstrated a good rate of successful predictions (74-92%, depending on the dataset and exact criterion used).
A simple pharmacophore point filter has been developed that discriminates between drug-like and nondrug-like chemical matter. It is based on the observation that nondrugs are often underfunctionalized. Therefore, a minimum count of well-defined pharmacophore points is required to pass the filter. The application of the filter results in 66-69% of subsets of the MDDR database to be classified as drug-like. Furthermore, 61-68% of subsets of the CMC database are classified as drug-like. In contrast, only 36% of the ACD are found to be drug-like. While these results are not quite as good as those obtained with recently described neural net approaches, the method used here has clear advantages. In contrast to a neural net approach and also in contrast to decision tree methods described recently, the pharmacophore filter has been developed by using "chemical wisdom" that is unbiased from fitting the structural content of specific drug databases to prediction models. Similar to decision tree methods, the pharmacophore point filter provides a detailed structural reason for the classification of each molecule as drug or nondrug. The pharmacophore point filter results are compared to neural net filter results. A statistically significant overlap between compounds recognized as drug-like validates both approaches. The pharmacophore point filter complements neural net approaches as well as property profiling approaches used as drug-likeness filters in compound library analysis and design.
Suspension cultures of Panax ginseng C.A. Meyer (Araliaceae) were treated with either an elicitor preparation from the culture broth of the phytopathogenic hyphomycete Botrytis cinerea or a yeast elicitor preparation, and the accumulation of a new compound, which was not detected in non-elicited cultures, was observed. The accumulated compound was isolated and shown to be 2,5-dimethoxy-1,4-benzoquinone by 1H-NMR, 13C-NMR and electron ionization (EI) mass spectra. While it is well known that this compound shows antibacterial activity against Staphylococcus aureus, its presence in ginseng root has not been reported to date. Levels of the compound in the media increased rapidly, reaching a maximum level of 65.10 +/- 4.96 microg/g fresh weight at approximately 12 h after treatment with the yeast elicitor preparation. The maximal level of the compound in medium from the culture treated with an elicitor preparation from the culture broth of B. cinerea was 46.13 +/- 10.42 microg/g fresh weight after 24 h of incubation.
Identification of organic compounds from plants is of clinical significance because of the effect that they might have in patients with haematopoietic disorders. We studied the effect of the plant extract Justicia spicigera (Acanthaceae) in different haematopoietic cells: human leukaemic cell lines, umbilical cord blood cells, and mouse bone marrow cells.
By examining colony formation and performing the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay it was shown that the plant extract of Justicia spicigera contains cytotoxic factors for leukaemic cells and has no proliferative activity on normal haematopoietic progenitor cells. Our results show that this plant extract induces apoptosis in the human leukaemia cell line TF-1, but not in the bcl-2 transfectant cell line TB-1. Similar results were obtained using a haemopoietic cell line 32D and 32DBcl2. The cultures of umbilical cord blood cells and mouse bone marrow that contain granulocyte-macrophage colony-stimulating factor (GM-CSF) do not proliferate or become terminally differentiated in the presence of the infusion of Justicia spicigera. GM-CSF that acts by abrogating programmed cell death is not sufficient to inhibit the apoptotic stimulus in TF-1 and 32D cells. Moreover mouse fibroblasts (3T3) and two cervical carcinoma cell lines CALO and INBL, undergo apoptosis in the presence of different concentrations of an infusion from the plant. Our data show that there is a strong correlation between the cytotoxic effect and cell proliferation. Together, these results indicate that the plant infusion of Justicia spicigera does not contain any haematopoietic activity, induces apoptosis inhibited by bcl-2 and is linked to cell proliferation. Copyright