A new sequential tristhiazole-thiazoline-containing cyclic peptide, marthiapeptide A (1), was isolated from a 60 L scale culture of the deep South China Sea-derived strain Marinactinospora thermotolerans SCSIO 00652. The planar structure and absolute configuration of 1 were elucidated by application of spectroscopic techniques, as well as by single-crystal X-ray diffraction and chiral-phase HPLC analysis of the acid hydrolysates. Marthiapeptide A (1) exhibited antibacterial activity against a panel of Gram-positive bacteria, with MIC values ranging from 2.0 to 8.0 μg/mL, and displayed strong cytotoxic activity against a panel of human cancer cell lines with IC(50) values ranging from 0.38 to 0.52 μM.
Elaiophylin (1) and two new methyl derivatives, 11-O-monomethylelaiophylin (2) and 11,11'-O-dimethylelaiophylin (3), were isolated from the mycelium cake of Streptomyces strains HKI-0113 and HKI-0114. The structures of 2 and 3 were determined by mass spectrometric and NMR investigations. Compounds 2 and 3 display antimicrobial and moderate cytotoxic activities.
The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety.
An exopolysaccharide (EPS) was isolated from Bacillus coagulans RK-02 and purified by size exclusion chromatography. The purified, homogeneous EPS had an average molecular weight of ∼3 × 10⁴ Da by comparison with FITC-labeled dextran standards. In vivo evaluations showed that, like other reported polysaccharides, this EPS displayed significant antioxidant activity. FTIR spectroscopy analysis showed the presence of hydroxy, carboxy, and α-glycosidic linkages and a mannose residue. GC analysis indicated that the EPS was a heteropolymer composed of glucose, mannose, galactose, glucosamine, and fucose as monomeric constituent units. Partial elucidation of the structure of the carbohydrate biopolymer based on GC-MS and NMR analysis showed the presence of two unique sets of tetrasaccharide repeating units that have 1→3 and 1→6 glycosidic linkages. This is also the first report of a Gram-positive bacterial polysaccharide with both fucose as a sugar monomer and 1→3 and 1→6 glycosidic linkages in the molecular backbone.
Analysis of the genome of Streptomyces aizunensis NRRL B-11277 indicated its potential to produce a compound of novel and highly predictable structure. The structure was predicted with sufficient accuracy to allow straightforward detection of the specific metabolite in HPLC profiles of fermentation extracts and hence to guide the isolation. The spectroscopic work was reduced to a confirmation of structure rather than a first principle determination. The compound, ECO-02301 (1), demonstrated potent antifungal activity. This work exemplifies not only the discovery of novel antibiotics from well-characterized organisms but also the utility of genomics as a further tool, complementary to spectroscopy, to enable rapid determination of complex structures.
Strain SpD081030SC-03, representing a novel species of Streptomyces, was isolated from a marine sponge. Two 3,5,6-trisubstituted 2(1H)-pyrazinones, JBIR-56 (1) and JBIR-57 (2), were isolated from a culture of SpD081030SC-03. The planar structures of 1 and 2 were assigned on the basis of extensive NMR and MS analyses. In addition, analyses of the methylated derivative of 1 confirmed a 3,5,6-trisubstituted 2(1H)-pyrazinone moiety. The absolute configurations of the amino acid residues were determined by application of Marfey's method. Because 1 did not appear to comprise the normal connection of amino acid units, we confirmed its structure by the total synthesis of 1. Biosynthetically, 1 consists of a unique skeleton connected to the peptide chain at C-5 of the pyrazinone ring.
Three new macrolactams, heronamides D-F (1-3), were isolated from the deep-sea-derived Streptomyces sp. SCSIO 03032 upon changing cultivation conditions. The planar structures of heronamides D-F (1-3) were elucidated by extensive MS and NMR spectroscopic analyses and comparisons with the closely related heronamides A-C. The relative configurations of 1-3 were deduced by detailed analysis of (3)JHH values and NOESY data. The absolute configurations of 1 and 2 were determined by chemical modifications and application of the modified Mosher's method. None of the compounds exhibited obvious antimicrobial or cytotoxic activities.
Exploration of marine-derived actinomycetes as a source of antitumor compounds has led to the isolation of a new member of the tartrolon series, tartrolon D (4). This new compound was obtained from Streptomyces sp. MDG-04-17-069 fermentation broths and displayed strong cytotoxic activity against three human tumor cell lines. Additionally, the known compound ikarugamycin (5) was also found in the culture broths of the same microorganism. The structure of this new tartrolon was established by a combination of spectroscopic techniques (1D and 2D NMR, HRMS, and UV) as well as by comparison with published data for similar compounds.
Four new antitumor pyranones, PM050511 (1), PM050463 (2), PM060054 (3), and PM060431 (4), were isolated from the cell extract of the marine-derived Streptomyces albus POR-04-15-053. Their structures were elucidated by a combination of spectroscopic methods, mainly 1D and 2D NMR and HRESIMS. They consist of an α-methoxy-γ-pyrone ring containing a highly substituted tetraene side chain glycosylated at C-10 in the case of 1 and 4. Compounds 1 and 4 displayed strong cytotoxicity against three human tumor cell lines with GI₅₀ values in the submicromolar range, whereas 2 showed subnanomolar activity as an inhibitor of EGFR-MAPK-AP1-mediated mitogenic signaling, causing inhibition of EGF-mediated AP1 trans-activation and EGF-mediated ERK activation and slight inhibition of EGF-mediated JNK activation. Taken together, these results suggest that members of the pyranone family of compounds could be developed as potential antitumor agents.
Six new prenylated polyhydroxy-p-terphenyl metabolites, named prenylterphenyllins A-C (1-3) and prenylcandidusins A-C (5-7), and one new polyhydroxy-p-terphenyl with a simple tricyclic C-18 skeleton, named 4''-dehydro-3-hydroxyterphenyllin (4), were obtained together with eight known analogues (8-15) from Aspergillus taichungensis ZHN-7-07, a root soil fungus isolated from the mangrove plant Acrostichum aureum. Their structures were determined by spectroscopic methods, and their cytotoxicity was evaluated using HL-60, A-549, and P-388 cell lines. Compounds 1 and 8 exhibited moderate activities against all three cell lines (IC50 1.53-10.90 μM), whereas compounds 4 and 6 displayed moderate activities only against the P-388 cell line (IC50 of 2.70 and 1.57 μM, respectively).
Two phenolic compounds, JBIR-94 (1) and JBIR-125 (2), were isolated from the fermentation broth of strain R56-07, which was identified by phylogenetic methods as a novel species of Streptomyces. The structures of 1 and 2 were assigned on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compounds 1 and 2 exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with an IC(50) value of 11.4 and 35.1 μM, respectively. These compounds are the first examples of hydroxycinnamic acid amides containing putrescine or spermidine produced by actinomycetes.
07H239-A (1), a new eremophilane sesquiterpene from a marine-derived xylariaceous fungus, was isolated, characterized, and shown to be cytotoxic toward a variety of cancer cell lines, with some selectivity for a CCRFCEM leukemia line (IC(50) = 0.9 microg/mL).
In the course of our continuing search for new antitumor-antibiotics from marine-derived actinomycete bacteria, four new cytotoxic compounds, designated as daryamides A (1), B (2), and C (3) and (2E,4E)-7-methylocta-2,4-dienoic acid amide (4), were isolated from the culture broth of a marine-derived Streptomyces strain CNQ-085. The structures of these new compounds were assigned by detailed interpretation of spectroscopic data. The relative configuration of 1 was determined by comprehensive NMR analysis, while the absolute configuration of 1 was determined as 4S,5R using the modified Mosher method. The daryamides show weak to moderate cytotoxic activity against the human colon carcinoma cell line HCT-116 and very weak antifungal activities against Candida albicans.
Eight drimane sesquiterpenes (1-8), six isochromane derivatives (9-14), and three known compounds, daldinin B (15), 9alpha-hydroxy-6beta-[(2E,4E,6E)-octa-2,4,6-trienoyloxy]-5alpha-drim-7-en-11,12-olide (16), and pergillin (17), were isolated from the EtOAc extract of the marine-derived fungus Aspergillus ustus 094102. The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxic effects on A549 and HL-60 cell lines were evaluated by SRB and MTT methods. Ustusorane E (13) showed significant cytotoxicity against HL-60 cells with an IC50 value of 0.13 microM. Ustusolates C (6) and E (8) exhibited moderate cytotoxicity against A549 and HL-60 cells with IC50 values of 10.5 and 9.0 microM, respectively, and ustusolate A (4) showed weak cytotoxicity against HL-60 and A549 cells with IC50 values of 20.6 and 30.0 microM, respectively.
As a part of our studies on the metabolism of natural compounds, gallic acid was orally administered to rats. The urinary metabolites were analyzed by high-performance liquid chromatography, and their structures were determined to be pyrogallol (M1), pyrogallol-1-O-beta-D-glucuronide (M2), 4-O-methylgallic acid-3-O-sulfate (M3), 2-O-methylpyrogallol-1-O-beta-D-glucuronide (M4), 2-O-methylpyrogallol (M5), 4-O-methylgallic acid (M6), and unchanged gallic acid on the basis of chemical and spectral data. The radical scavenging effects of gallic acid and its urinary metabolites were evaluated using 1,1-diphenyl-2-picrylhydrazyl radical.
A study of the coloring matter produced by Conidiobolus paulus Drechsler NRRL 2648 on potato-dextrose medium led to the isolation of a new dialdehyde unsaturated metabolite, (all trans)-2,4,6,8,10,12-tetradeca-1,14-hexenedial. The structure was characterized by MS and by 1H- and 13C-NMR. The compound inhibited the growth of the Gram-positive bacterium, Bacillus cereus, and the Gram-negative bacterium, Escherichia coli (MIC values of 10 micrograms and 50 micrograms, respectively).
Three new 1,19-seco-avermectin (AVE) analogues were isolated from the ΔaveCDE mutant Streptomyces avermectinius strain. Their structures were elucidated by detailed spectroscopic analysis. This is the first report of 1,19-seco-AVE analogues. In an in vitro assay these compounds displayed cytotoxicity against Saos-2, MG-63, and B16 cell lines.
The synthesis of (+/-)-11alpha-hydroxy-3-oxo-6alphaH,7alphaH, 10betaMe-eudesman-1,2-4,5-dien-6,12-olide (1), previously isolated from Melanoselinum decipiens, is described, and its structure has been corrected.
Two new seco-prezizaane-type sesquiterpenes, 1,2-dehydroneomajucin (1) and jiadifenin (2), were isolated from the methanol extract of the pericarps of Illicium jiadifengpi, indigenous to the southern part of China. Their structures were elucidated on the basis of NMR data. Compound 2, which is an equilibrated mixture of the epimers 2a and 2b on the C-10 acetal carbon, is the first example of a majucin-type seco-prezizaane with an oxo-function at the C-10 position. The proposed structure for 2 was unambiguously confirmed by chemical conversion of the known sesquiterpene (2S)-hydroxy-3,4-dehydroneomajucin (5) to 2. Compounds 2 and 5 were found to significantly promote neurite outgrowth in primary cultures of fetal rat cortical neurons at concentrations from 0.1 to 10 microM.
From the hydrophobic fraction of the latex of Hippomane mancinella, weak or nonirritant mixtures of esters of polyfunctional diterpene parent alcohols of the tigliane and daphnane types were isolated belonging to the structural type of "cryptic" irritants. The cryptic factor group M'z (tigliane type) represents 12-deoxyphorbol-13,20-diesters, and the cryptic factor groups M'y and M'x (daphnane type) represent mixtures of 9,13,14-orthoesters-20-esters of resiniferonol and 5 beta-hydroxyresiniferonol-6 alpha,7 alpha-oxide, respectively. All of them carry in the 20-position homologous long-chain fatty acids, ranging from C15 to C26. They may be "activated" by mild transesterification reactions yielding corresponding irritant factor groups with free hydroxyl functions at C-20. From the hydrophilic fraction of the latex, the irritant factor M3 (tigliane type) and the factor group Mx (daphnane type) were isolated. According to spectral data, factor M3 represents the 13-(hexadeca-2,4,6-trienoic acid) ester of the parent 12-deoxy-5 beta-hydroxyphorbol-6 alpha,7 alpha-oxide. Factor group Mx consists of two esters inseparable by tlc (silica gel). One is identical with huratoxin; the other represents a hexadeca-2,4,6-trienoic acid orthoester. Mx is also obtained by transesterification of M'x and exhibits irritant and tumor-promoting activity comparable to that of TPA. Some aspects on structure activity relations are deduced from selected chemical-reaction products of factor group Mx.
Permanganate oxidation of acronycine (1) led to keto alcohol 4 which could be reduced to trans-1,2-dihydroxy-1,2-dihydroacronycine (3) using NaBH4. Acylation of 3 afforded 12, 13, and 14. These esters (12, 13, and 14) were more potent than 1 when tested against L-1210 cells in vitro. Diacetate 12 was evaluated in vivo against murine P-388 leukemia and was markedly active at a dose 16-fold lower than acronycine itself. Comparison of these results with those recently obtained in the cis-1,2-dihydroxy-1,2-dihydroacronycine series is discussed.
Two 1,2-bis(4-hydroxy-3-methoxyphenyl)-1,3-propanediol 1-O-glucosides, hovetrichosides A (1) and B (2), were isolated from the bark of Hovenia trichocarpa. Their structures were established by extensive NMR experiments and chemical methods. Compounds 1 and 2 were (1R), (2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)-1, 3-propanediol 1-O-beta-D-glucopyranoside and (1S), (2R)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenyl)-1, 3-propanediol 1-O-beta-D-glucopyranoside, respectively.
A new pentacyclic Stemona alkaloid, stemocurtisinol (3), with a pyrido[1,2-a]azepine A,B-ring system, and the known pyrrolo[1,2-a]azepine alkaloid oxyprotostemonine (4) have been isolated from a root extract of S. curtisii. The structure and relative stereochemistry of stemocurtisinol was determined by spectral data interpretation and X-ray crystallography. This compound is a diastereoisomer of oxystemokerrin and has the opposite configuration at C-4 and C-19. The individual alkaloid components showed significant larvicidal activity (IC(50) 4-39 ppm) on mosquito larvae (Anopheles minimus HO).
Calyxamines A (1) and B (2) are 2,2,4,6,6-pentasubstituted piperidine alkaloids possessing novel carbon skeletons isolated from the marine sponge Calyx podatypa collected in Puerto Rico. Their structures, after derivatization with trifluoroacetic acid, have been determined by a combination of X-ray and spectroscopic methods. A plausible biogenetic pathway to the calyxamines is suggested.
Calyxolanes A (1) and B (2) are rare 1,3-diphenylbutanoid compounds isolated from the marine sponge Calyx podatypa collected in Puerto Rico. Their structures, including relative stereochemistry, have been determined by spectroscopic methods. The unique 2,4-diphenyloxolane function in 1 and 2 was established by 2D 1H-1H and 1H-13C NMR correlation experiments and confirmed by mass spectral analysis. A suggestion is made as to their biogenetic origin.
Two new diphenylpropan-1,2-diols, eryvarinols A (1) and B (2), were isolated from the roots of Erythrina variegata. Their structures were elucidated as 1-(4-hydroxy-2-methoxyphenyl)-2-(4-hydroxy-3,5-dimethoxybenzoyloxy)-3-(4-hydroxyphenyl)propan-1-ol (1) and its 3"-prenyl derivative (2) on the basis of spectroscopic and chemical evidence. Both these compounds are unusual diphenylpropan-1,2-diols with a syringyl group.
1,2-Bis(1H-indol-3-yl)ethane-1,2-dione (1), a bisindole alkaloid, was isolated from the marine sponge Smenospongia sp. The known compounds indole-3-carbaldehyde (2), 6-bromoindole-3-carbaldehyde (3), and tryptamine (4) and mixtures of the (Z/E) isomers of 6-bromo-2'-demethylaplysinopsin (5a/5b) and 6-bromo-3'-deimino-2',4'-bis(demethyl)-3'-oxoaplysinopsin (6a/6b) were also isolated.
It is shown that geneserine [2] and geneseroline [4] convert with acid into salts of physostigmine N-oxide [3] and geneseroline N-oxide [5], respectively. Structure assignments were made on the basis of chemical conversions, 1H-nmr analysis of 2-5, and an X-ray analysis of 5 as its hydrochloride.
Two new cyclic peroxide-containing polyketide C16 acids 2 and 4 with their methyl esters 3 and 5 have been isolated from the Indo-Pacific marine sponge Plakortis aff. simplex. Both 2 and 3 are proposed to contain a single 1,2-dioxene ring, while 4 and 5 incorporate two 1,2-dioxene rings. The structures were elucidated mainly through 1D and 2D nmr spectral analysis. The methyl esters 3 and 5 were found to be active against cultured P-388 murine leukemia cells.
2-Methylnaphtho[1,2-d]oxazole-9-carboxylic acid was obtained by reduction of 8-nitro-1-naphthoic acid with zinc-acetic acid. This naphthoxazole is a condensation product between an 8-nitro-1-naphthoic acid reduction intermediate and acetic acid and is a lower homologue of aristoxazole, a similar condensation product of aristolochic acid I with acetic acid that was previously reported. Both oxazoles are believed to arise via a common nitrenium/carbocation ion mechanism that is likely related to that which leads to aristolochic acid-DNA-adducts.
The history of the development of the important anticancer drug taxol (1) is briefly described, and recent studies of its chemistry and tubulin-binding conformation are then presented. Topics discussed include side chain attachment to baccatin III (3a), the effect of oxygenation of the taxane ring system on bioactivity, the importance of the oxetane ring for bioactivity, the synthesis of a C-6/C-4 bridged analogue, and the conformation of the side chain when taxol is bound in a complex with polymerized tubulin.
The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).
A systematic structure-activity relationship study of plicatin B (1), an antimutagenic constituent of Psoralea juncea, was undertaken with a view toward elucidating its chemical mode of action and possibly optimizing its antimutagenic activity during the process. Compound 1 and its related analogues were examined for their antimutagenic activity against mutations induced by ethyl methanesulfonate, a direct acting mutagen and alkylating agent, in Salmonella typhimurium strain TA100, utilizing the modified Ames test protocol. The dihydro analogue 3 resulting from saturation of the conjugated alkene double bond of 1 was found to exhibit reduced cytotoxicity and enhanced efficacy relative to the parent compound. This result serves preliminarily to exclude a Michael acceptor role of the alpha,beta-unsaturated carbonyl moiety in connection with its antimutagenic activity.
A new chemical study of the Caribbean gorgonian Eunicea succinea collected in Puerto Rico afforded seven new cembranolides (1-5, 7, and 8). Excepting 1, the new compounds described here possess an unusual unsaturation at either position C-1, C-6, or C-8, and all but 8 possess the C-12R, C-13S stereochemistry usually ascribed to cembranolides from E. succinea. Their chemical structures were carefully established by a combination of chemical and spectroscopic methods in addition to detailed NMR spectral comparisons with known cembranolide models.
A new 1,2-dihydroisoquinoline (1) and a known isoquinolinequinone (2) have been isolated from the sponge Petrosia similis and characterized by the study of spectral data.
The aqueous ethanolic extract from the roots of Stellaria dichotoma showed an antiallergic effect on ear passive cutaneous anaphylaxis (PCA) reaction in mice (in vivo) and inhibitory activity on the release of beta-hexosaminidase in RBL-2H3 cells (in vitro). From the aqueous ethanolic extract, new beta-carboline-type alkaloids, dichotomines A (1), B (2), C (3), and D (4) and dichotomides I (5) and II (6), were isolated. The structures of the new constituents (1-6) were determined on the basis of chemical and physicochemical evidence, including the application of the modified Mosher's method. The effects of the isolated constituents on the release of beta-hexosaminidase in RBL-2H3 cells were examined, and 3 was found to show inhibitory activity (IC(50) = 62 microM). Moreover, 3 also inhibited the releases of antigen-IgE-mediated TNF-alpha and IL-4 (19 and 15 microM, respectively) in RBL-2H3 cells, both of which participate in the late phase of type I allergic reactions.
Recently, we reported that 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (AM6-36), sharing structural similarity with naturally occurring isoquinolines, induced activities mediated by retinoid X receptor (RXR) response element accompanied by antiproliferative effects on breast cancer cells. To further characterize the biologic potential of AM6-36, we currently report studies conducted with HL-60 human leukemia cells. AM6-36 significantly inhibited cellular proliferation in a dose- and time-dependent manner with an IC(50) value of 86 nM. When evaluated at low test concentrations (≤0.25 μM), AM6-36 induced arrest in the G2/M phase of the cell cycle. At higher concentrations (1 and 2 μM), the response shifted to apoptosis, which was consistent with the effect of AM6-36 on other apoptotic signatures including an increase of apoptotic annexin V(+) 7-AAD(-) cells, loss of mitochondrial membrane potential, induction of poly(ADP-ribose) polymerase cleavage, and activation of several caspases. These apoptotic effects are potentially due to up-regulation of p38 MAPK and JNK phosphorylation and down-regulation of c-Myc oncogene expression. Taken together, AM6-36 might serve as an effective anticancer agent by inducing G2/M cell cycle arrest and apoptosis through the activation of MAPKs and inhibition of c-Myc.
A recent collection and extraction of the common Caribbean sea whip Eunicea succinea from Puerto Rico has produced four previously undescribed representatives of the cembrane family of diterpenes (2, 3, 4, and 6). A new geranylgeraniol derivative, 8, was also isolated as a minor constituent. The chemical structures of the new compounds were carefully established by spectroscopic and chemical methods in addition to detailed NMR spectral comparisons with known cembranoid models from Eunicea.
Two new cyclic peroxide-containing polyketide C22 methyl esters, peroxyacarnoic acid methyl esters A and B, 1 and 2, have been isolated from the Red Sea marine sponge Acarnus cf. bergquistae. Both 1 and 2 are proposed to contain a single 1,2-dioxane ring, an eneyne functionality, and a terminal double bond or triple bond, respectively. The structures were elucidated mainly through 1D and 2D NMR spectral analysis.
A new pentacyclic stemona alkaloid, stemocurtisine (2), with a novel pyrido[1,2-a]azapine A,B-ring system, has been isolated from a root extract of Stemona curtisii. The structure and relative stereochemistry was determined by spectral data interpretation and X-ray crystallography.
The major cytotoxic activity of crude extracts of Nectandra rigida Nees is due to dehydrodiisoeugenol,the sample isolated being slightly enriched in the dextrorotatory enantiomer. Galgravin and two new tetrahydrofuranoid lignans, nectandrin A and nectandrin B, were also isolated and characterized along with small quantities of vanillin, 2,6-dimethoxybenzoquinone, and the known lauraceous alkaloid laurelliptine. The neolignans are of potential chemotaxonomic significance in the study of the Lauraceae.
The new endoperoxyketal polyketides manadoperoxides A-D (2-5) have been isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin (1) and peroxyplakoric B(3) ester (9), the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and production of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.
The 7-(4-aminomethyl-1H-1,2,3-triazol-1-yl) analogue of kabiramide C (5) was synthesized by using the Mitsunobu reaction and 1,3-dipolar cycloaddition. This compound and the intermediate compounds 2 and 4 were shown to bind tightly to G-actin in a 1:1 complex and exhibited the same degree of cytotoxicity as 1. Compound 5 serves as a key intermediate for the synthesis of actin-directed optical probes and drugs.
The inhibition of protein tyrosine phosphatase 1B (PTP1B) is of substantial interest for the treatment of type-2 diabetes mellitus. Using an in vitro enzyme assay with human recombinant PTP1B 1,2,3,4,6-penta-O-galloyl-D-glucopyranose was isolated from the roots of Paeonia lactiflora as an inhibitor of PTP1B, with an IC(50) value of 4.8 μM. Additionally, 1 was shown to act as an insulin sensitizer in human hepatoma cells (HCC-1.2) at a concentration of 10 μM. Thus, a potential new mechanism of action is provided explaining the antidiabetic properties of P. lactiflora.
The new purine 1,3,7-trimethylisoguanine (1) has been isolated from the ascidian Pseudodistoma cereum. The structure of 1 was elucidated by analysis of NMR spectroscopic and mass spectrometric data and by comparison with the regioisomeric purine 1,3,7-trimethylguanine (2).
The structures of three new compounds isolated from Peperomia proctorii, named proctoriones A-C, have been established by spectroscopic and chemical methods as 2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec-(11Z)-enoylcyclohexane-1,3-dione (3).
A new purine, 1,3-dimethylisoguanine (1), has been isolated from the marine sponge Amphimedon viridis and identified by analysis of spectroscopic data. Compound 1 increased the contractions obtained by transmural electrical stimulation in the guinea pig longitudinal muscle/myenteric plexus in a dose-dependent manner.
