Showing papers in "Journal of Natural Products in 2003"

Natural Products as Sources of New Drugs over the Period 1981−2002

Abstract: This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are bas...

Marine natural products as novel antioxidant prototypes.

Abstract: Pure natural products isolated from marine sponges, algae, and cyanobacteria were examined for antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) solution-based chemical assay and a 2‘,7‘-dichlorodihydrofluorescein diacetate (DCFH-DA) cellular-based assay. The DCFH system detects only antioxidants that penetrate cellular membranes. Potent antioxidants were identified and the results from each system compared. The algal metabolites cymopol (1), avrainvilleol (3), and fragilamide (4), and the invertebrate constituent puupehenone (5) showed strong antioxidant activity in both systems. Several compounds were active in the DPPH assay but significantly less active in the DCFH system. The green algal metabolite 7-hydroxycymopol (2) was isolated from Cymopolia barbata and its structure determined. Compound 2 was significantly less active in the DCFH system than cymopol (1). The sponge metabolites (1S)-(+)-curcuphenol (6), aaptamine (7), isoaaptamine (8), and curcudiol (9) and the cyanobacte...

Molecular structure and stereochemistry of silybin a, silybin b, isosilybin a, and isosilybin b, isolated from silybum marianum (milk thistle)

Abstract: Two pairs of diastereoisomeric flavonolignans, silybin A, silybin B, isosilybin A, and isosilybin B, were successfully separated from Silybum marianum by sequential silica gel column chromatography, preparative reversed-phase HPLC, and recrystallization. Complete stereochemical assignments at C-2, C-3, C-7‘, and C-8‘ of these flavonolignans have been achieved. On the basis of X-ray crystallographic analysis and optical rotation data, coupled with comprehensive 1H and 13C NMR spectral data interpretation including COSY, HMQC, and HMBC, the stereochemistry of these diastereoisomers was determined unambiguously as silybin A (4), 2R, 3R, 7‘R, 8‘R; silybin B (5), 2R, 3R, 7‘S, 8‘S; isosilybin A (6), 2R, 3R, 7‘R, 8‘R; and isosilybin B (7), 2R, 3R, 7‘S, 8‘S.

dd-diketopiperazines: antibiotics active against Vibrio anguillarum isolated from marine bacteria associated with cultures of Pecten maximus.

Abstract: Bacterial strains CF-20 (CECT5719) and C-148 (CECT5718), isolated from cultures of larvae of molluscs, are shown to produce substances 1-5 with strong antibiotic activity against Vibrio anguillarum (MIC: 0.03-0.07 mug/mL) and identified as the dd-diketopiperazines cyclo(d)-Pro-(d)-Phe (1), cyclo(d)-Pro-(d)-Leu (2), cyclo(d)-Pro-(d)-Val (3), cyclo(d)-Pro-(d)-Ile (4), and cyclo-trans-4-OH-(d)-Pro-(d)-Phe (5). Comparison with other stereoisomers indicates that inhibition of V. anguillarum is associated with the presence of at least one d-amino acid in the diketopiperazine system. This is the first time a series of dd-diketopiperazines has been isolated from a single natural source and their inhibitory activity against V. anguillarum described.

Antihyperglycemic effect of puerarin in streptozotocin-induced diabetic rats.

Abstract: The antihyperglycemic action of puerarin, purified from the roots of Pueraria lobata, was investigated in streptozotocin-induced diabetic rats (STZ-diabetic rats). Bolus intravenous injection of puerarin decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Similar treatment with puerarin also decreased the plasma glucose in normal rats, although the effect was not as great as that in STZ-diabetic rats. Puerarin at the effective dose (15.0 mg/kg) significantly attenuated the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. In the isolated soleus muscle of STZ-diabetic rats, puerarin enhanced the uptake of radioactive glucose in a concentration-dependent manner. Moreover, the mRNA and protein levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle were increased after repeated intravenous administration of puerarin in STZ-diabetic rats for 3 days. These results suggest that puerarin can increase the glucose utilization to lower plasma glucose in diabetic rats lacking insulin.

Imidazole alkaloids from Lepidium meyenii.

Abstract: Two new imidazole alkaloids (lepidiline A and lepidiline B) have been isolated from a root extract of Lepidium meyenii with the common name Maca and identified as 1,3-dibenzyl-4,5-dimethylimidazolium chloride (1) and 1,3-dibenzyl-2,4,5-trimethylimidazolium chloride (2), respectively. The structures of these two new compounds were determined by spectroscopic methods, as well as single-crystal X-ray diffraction performed on compound 1.

Induction of apoptosis by xanthones from mangosteen in human leukemia cell lines.

Abstract: We examined the effects of six xanthones from the pericarps of mangosteen, Garcinia mangostana, on the cell growth inhibition of human leukemia cell line HL60. All xanthones displayed growth inhibitory effects. Among them, α-mangostin showed complete inhibition at 10 μM through the induction of apoptosis.

An Antiinflammatory Galactolipid from Rose Hip (Rosa canina) that Inhibits Chemotaxis of Human Peripheral Blood Neutrophils in Vitro

Abstract: The galactolipid (2S)-1,2-di-O-[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl]-3-O-beta-d-galactopyranosyl glycerol (1) isolated from dried and milled fruits of Rosa canina by bioassay-guided fractionation is an antiinflammatory agent with inhibitory effects on chemotaxis of human peripheral blood neutrophils in vitro. The inhibition of cell migration is not related to toxicity. The presence of 1 in rose hips may explain the clinically observed antiinflammatory properties of rose hip herbal remedies.

Bioactive novel polyphenols from the fruit of Manilkara zapota (Sapodilla).

Abstract: Activity-guided fractionation of a methanol extract from the fruit of Manilkara zapota cv. Tikal resulted in the isolation of two new antioxidants, methyl 4-O-galloylchlorogenate (1) and 4-O-galloylchlorogenic acid (2), along with eight known polyphenolic antioxidants, namely, methyl chlorogenate (3), dihydromyricetin (4), quercitrin (5), myricitrin (6), (+)-catechin (7), (−)-epicatechin (8), (+)-gallocatechin (9), and gallic acid (10). Of the 10 polyphenols, 1 showed the highest antioxidant activity (IC50 = 12.9 μM) in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assay and displayed cytotoxicity in the HCT-116 and SW-480 human colon cancer cell lines with IC50 values of 190 and 160 μM, respectively. Compound 2 showed high antioxidant activity (IC50 = 23.5 μM) in the DPPH free-radical assay and displayed cytotoxicity in the HCT-116 and SW-480 human colon cancer cell lines with IC50 values of 154 and 134 μM, respectively.

Cytotoxic and antimalarial β-carboline alkaloids from the roots of Eurycoma longifolia

Abstract: Three new [n-pentyl β-carboline-1-propionate (1), 5-hydroxymethyl-9-methoxycanthin-6-one (2), and 1-hydroxy-9-methoxycanthin-6-one (3)] and 19 known β-carboline alkaloids were isolated from the roots of Eurycoma longifolia. The new structures were determined by comprehensive analyses of their 1D and 2D NMR and mass spectral data and by chemical transformation. These compounds were screened for in vitro cytotoxic and antimalarial activities, and 9-methoxycanthin-6-one (4) and canthin-6-one (5) demonstrated significant cytotoxicity against human lung cancer (A-549) and human breast cancer (MCF-7) cell lines.

Structures of new dammarane-type Triterpene Saponins from the flower buds of Panax notoginseng and hepatoprotective effects of principal Ginseng Saponins.

Abstract: The saponin fraction from the flower buds of Panax notoginseng exhibited protective effect on liver injury induced by d-galactosamine and lipopolysaccharide. From the saponin fraction with hepatoprotective effect, five new dammarane-type triterpene saponins, notoginsenosides-O (1), -P (2), -Q (3), -S (4), and -T (5), were isolated together with nine known protopanaxadiol oligoglycosides. The structures of the new saponins were elucidated on the basis of chemical and physicochemical evidence. The principal dammarane-type triterpene saponins from the roots and flower buds of Panax notoginseng were found to show potent hepatoprotective effects.

Trichodermamides A and B, cytotoxic modified dipeptides from the marine-derived fungus Trichoderma virens.

Abstract: Trichodermamides A (1) and B (2), two modified dipeptides, have been isolated from cultures of the marine-derived fungus Trichoderma virens. The trichodermamides possess a rare cyclic O-alkyl-oxime functionality incorporated into a six-membered ring. The structure of trichodermamide B was established by X-ray diffraction analysis, while the structure assignment of trichodermamide A, and determination of the absolute stereochemistry, was accomplished by spectral and chemical methods. Trichodermamide B displayed significant in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC(50) of 0.32 microg/mL.

Cytotoxic sesquiterpene lactones from the root of Saussurea lappa.

Abstract: Bioassay-directed fractionation of Saussurea lappa led to the isolation of a novel lappadilactone (1) and seven sesquiterpene lactones (2-8) as cytotoxic principles against selected human cancer cell lines. Lappadilactone (1), dehydrocostuslactone (2), and costunolide (5) exhibited the most potent cytotoxicity with CD50 values in the range 1.6-3.5 microg/mL in dose- and time-dependent manners. The cytotoxicities were not specific and showed similar activities against HepG2, OVCAR-3 and HeLa cell lines. The structure-activity relationship showed that the alpha-methylene-gamma-lactone moiety is necessary for cytotoxicity, and activity is reduced with the presence of a hydroxyl group. In addition, seven noncytotoxic compounds (9-15) were also isolated, including two novel sesquiterpenes, a guaianolide-type with a C17 skeleton, lappalone (13), and 1beta,6alpha-dihydroxycostic acid ethyl ester (14). The structures of the new compounds were elucidated from spectroscopic and/or X-ray data interpretations. Some representative compounds were also tested for antibacterial activity; however, only marginal activities were observed. Therefore, compounds 1-8 are potential cytotoxic agents but without significant antibacterial effect.

Pochonins A-F, new antiviral and antiparasitic resorcylic acid lactones from Pochonia chlamydosporia var. catenulata.

Abstract: Monorden (1) and the novel resorcylic acid lactones pochonins A (2), B (4), C (6), D (7), and E (8) as well as tetrahydromonorden (5) and pseurotin A (22) were isolated from cultures of the clavicipitaceous hyphomycete Pochonia chlamydosporia var. catenulata strain P 0297. Fermentation of P 0297 in bromide-containing culture media led to a shift in secondary metabolite production and yielded monocillins III (3) and II (9) as major metabolites besides monorden (1) as well as the novel compounds pochonin F (10) and a monocillin II glycoside (11) as minor metabolites. Most of these compounds showed moderate activities in a cellular replication assay against Herpes Simplex Virus 1 (HSV1) and against the parasitic protozoan Eimeria tenella. In contrast to the structurally related zearalenone derivatives none of the metabolites of strain P 0297 were found to be active in a fluorescence polarization assay for determination of modulatory activities on the human estrogenic receptor ERβ. β-Zearalenol (17), but not ...

New Manzamine Alkaloids with Activity against Infectious and Tropical Parasitic Diseases from an Indonesian Sponge

Abstract: Eleven manzamine type alkaloids, two beta-carbolines, and five nucleosides have been isolated from an Indonesian sponge Among these are the previously characterized 12,34-oxamanzamine A, 12,34-oxamanzamine E, manzamine A (1), 8-hydroxymanzamine A, 6-deoxymanzamine X, manzamine E (2), manzamine X, manzamine F (4), norharman, thymine, 2',3'-didehydro-2',3'-dideoxyuridine, uracil, thymidine, and 2'-deoxyuridine The structures for the five new compounds have been assigned as 32,33-dihydro-31-hydroxymanzamine A (3), 32,33-dihydro-6-hydroxymanzamine A-35-one (5), des-N-methylxestomanzamine A (6), 32,33-dihydro-6,31-dihydroxymanzamine A (7), and 1,2,3,4-tetrahydronorharman-1-one (8), on the basis of NMR and X-ray data The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented The structural revision of two previously reported pyrazoles as uracil and thymine is also discussed

Intercedensides A-C, three new cytotoxic triterpene glycosides from the sea cucumber Mensamaria intercedens Lampert.

Abstract: Three new triterpene glycosides, intercedensides A (1), B (2), and C (3), were isolated from the sea cucumber Mensamria intercedens Lampert, which is found in the South China Sea, and their structures have been elucidated by spectroscopic analysis (NMR and ESIMS) and chemical transformations. Intercedensides A (1) and C (3) have a conjugated double bond (22E,24-diene) in the side chain of the aglycon. Intercedenside B (2) has two beta-D-xylose and two sulfate groups in the carbohydrate chain. All three glycosides showed significant cytotoxicity against 10 human tumor cell lines with ED(50) in the range 0.6-4.0 microg/mL. Intercedenside A (1) exhibited significant in vivo antineoplastic activity against mouse Lewis lung cancer and mouse S180 sarcoma. On the basis of these initially promising results, intercedensides A-C merit further study as potential anticancer agents.

Antioxidative meroterpenoids from the brown alga Cystoseira crinita.

Abstract: Six new tetraprenyltoluquinol derivatives (1-6), two new triprenyltoluquinol derivatives (7 and 8), and two new tetraprenyltoluquinone derivatives (9 and 10) were isolated from the brown alga Cystoseira crinita Duby together with four known tetraprenyltoluquinol derivatives (11-14). All structures were elucidated by employing spectroscopic techniques (NMR, MS, UV, and IR). Each compound was evaluated for its antioxidative properties in the TBARS and DPPH assay, and compounds 1, 2, 6, and 10-14 were additionally assessed in the TEAC and PCL assay. Hydroquinones were found to have powerful antioxidant activity.

Cytotoxic prenylflavanones from Taiwanese propolis.

Abstract: Two new prenylflavanones, propolin A (2) and propolin B (3), were isolated and characterized from Taiwanese propolis. Both compounds were found to have cytotoxic properties against three cancer cell lines. DNA content analyses and DNA fragmentation indicated that propolin A (2) efficiently induced apoptosis in cancer cell lines, but had no effect on the cell cycle program. Furthermore, both propolin A (2) and B (3) are potential antioxidant agents and show strong scavenging effects against most types of free radicals.

New indole alkaloids from the North Sea bacterium Vibrio parahaemolyticus Bio249.

Abstract: Several bis- and tris-indole derivatives were isolated from a North Sea bacterium that was closely related to Vibrio parahaemolyticus (98% homology). 1,1,3-Tris(3-indolyl)butane (3) is a new compound, and 3,3-bis(3-indolyl)butane-2-one (1a), arundine (1b), and 1,1,1-tris(3-indolyl)methane (2a) were isolated from a microorganism for the first time here. Additionally, many other known compounds were obtained from the ethyl acetate extract of the culture. Their structures were established on the basis of various spectral data, and their origin is discussed. All compounds were inactive against a range of bacteria and fungi.

Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues.

Abstract: The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin (1), and consequently it has been subjected to thorough preclinical evaluation and targeted for clinical evaluation. The details of the synthesis of hemiasterlin (1) and the analogues and a discussion of how their biological activities vary with their structures are presented in this paper.

Euphane and tirucallane triterpenes from the roots of Euphorbia kansui and their in vitro effects on the cell division of Xenopus.

Abstract: Four new euphane-type triterpenes, kansenone (1), kansenonol (3), 11-oxo-kansenonol (4), kansenol (5), and a new tirucallane-type triterpene, epi-kansenone (2), were isolated from a 60% EtOH extract of Euphorbia kansui, together with alpha-euphol. Their structures were elucidated on the basis of extensive analysis of their 1D and 2D NMR spectral data. This appears to be the first report of the natural occurrence of euphane/tirucallane-type triterpenes with a ketone at C-7. In vitro treatment of cultured individual Xenopus laevis cells at the blastular stage with 1-4 significantly arrested cleavage of the cells (10 microg/mL of each compound resulted in >50% cleavage arrest).

Two new xanthone derivatives from the algicolous marine fungus Wardomyces anomalus

Abstract: A marine fungal isolate, identified as Wardomyces anomalus, was cultivated and found to produce two new xanthone derivatives, 2,3,6,8-tetrahydroxy-1-methylxanthone (1) and 2,3,4,6,8-pentahydroxy-1-methylxanthone (2), in addition to the known xanthone derivative 3,6,8-trihydroxy-1-methylxanthone (3) and the known fungal metabolite 5-(hydroxymethyl)-2-furanocarboxylic acid (4). The structures of all compounds were determined on the basis of extensive spectroscopic measurements (1D and 2D NMR, MS, UV, and IR). Compounds 1 and 4 showed significant antioxidant activities. The total extract and 1, 3, and 4 were shown to be inhibitors of p56lck tyrosine kinase.

Antimalarial dihydroisocoumarins produced by Geotrichum sp., an endophytic fungus of Crassocephalum crepidioides.

Abstract: Three novel dihydroisocoumarin derivatives (1-3) with antimalarial, antituberculous, and antifungal activities have been isolated by bioassay-guided fractionation from an endophytic fungus, Geotrichum sp., collected from Crassocephalum crepidioides. Structures were established as 7-butyl-6,8-dihydroxy-3(R)-pent-11-enylisochroman-1-one (1), 7-but-15-enyl-6,8-dihydroxy-3(R)-pent-11-enylisochroman-1-one (2), and 7-butyl-6,8-dihydroxy-3(R)-pentylisochroman-1-one (3) using spectroscopic data.

Novel tetramic acids and pyridone alkaloids, militarinones B, C, and D, from the insect pathogenic fungus Paecilomyces militaris.

Abstract: Three yellow pigments were isolated from a mycelial extract of the entomopathogenic fungus Paecilomyces militaris. With the aid of spectroscopic means, one compound was identified as a new pyridone alkaloid, militarinone D (1). The two other metabolites were characterized as two novel 3-acyl tetramic acids, militarinones B (2) and C (3). In contrast to the structurally related pyridone militarinone A (4), compounds 1-3 showed only negliable neuritogenic activity in PC-12 cells, whereas militarinone D (1) exhibited cytotoxicity. On the basis of a co-occurrence of 3-acyl tetramic acids and biogenetically related pyridone alkaloids in P. militaris, a revised biosynthetic pathway for pyridone alkaloids is proposed.

New 9-thiocyanatopupukeanane sesquiterpenes from the nudibranch Phyllidia varicosa and its sponge-prey Axinyssa aculeata

Abstract: Two new 9-thiocyanatopupukeanane sesquiterpene isomers were isolated as major metabolites from the MeOH extract of the sponge Axinyssa aculeata and from its nudibranch predator Phyllidia varicosa. The presence of the sesquiterpenes was monitored by GC-MS, and the structures were confirmed by both 1D and 2D NMR spectroscopy. The isolated sesquiterpenes were found to be toxic toward brine shrimp at LC(50) of 5 ppm. At a dose level of 20 microg, they were found to be weakly and moderately active against B. subtilis and C. albicans, respectively.

The macrocidins: novel cyclic tetramic acids with herbicidal activity produced by Phoma macrostoma.

Abstract: Field isolates of Phoma macrostoma were obtained from diseased Canada thistle growing in several geographically diverse regions. Bleaching and chlorotic symptoms were present on the infected plants. The isolates grown in liquid culture were found to produce phytotoxic metabolites which also caused bleaching when applied foliarly to several broadleaf species. Bioassay-directed isolation led to the discovery of macrocidins A and B, the first representatives of a new family of cyclic tetramic acids. This new chemotype may offer significant potential as a template for herbicide design.

Polyprenylated Benzophenones from Garcinia assigu and Their Potential Cancer Chemopreventive Activities

Abstract: In a further study on the chemical constituents of Garcinia assigu, two new benzophenones corresponding to the 13-O-methyl ethers (1 and 2) of the known isogarcinol and garcinol, respectively, were...

The leupyrrins: a structurally unique family of secondary metabolites from the myxobacterium Sorangium cellulosum.

Abstract: The structurally unique leupyrrins A1 (1), A2 (2), B1 (3), B2 (4), C (5), and D (6) were isolated as one of three groups of secondary metabolites from Sorangium cellulosum strains So ce705 and So ce690. An unusually substituted γ-butyrolactone ring and pyrrole and oxazoline rings are embedded in a nonsymmetric macrodiolide core structure, giving rise to compounds 1−6 as members of a novel class of secondary metabolites. Leupyrrin A1 (1) shows good biological activity against various fungi and eukaryotic cells.

Crambescidin 826 and dehydrocrambine A: new polycyclic guanidine alkaloids from the marine sponge Monanchora sp. that inhibit HIV-1 fusion.

Abstract: Two new polycyclic guanidine alkaloids, crambescidin 826 (1) and dehydrocrambine A (2), and the known compounds crambescidin 800 (3) and fromiamycalin (4) were isolated from the marine sponge Monanchora sp. The structures of 1 and 2 were elucidated by 2D NMR and mass spectrometry, and relative stereochemistry was established by analysis of coupling constants and ROESY spectra. The pentacyclic guanidine alkaloids 1, 3, and 4 inhibit HIV-1 envelope-mediated fusion in vitro with IC(50)'s of 1-3 microM, while compound 2, a tricyclic guanidine alkaloid, showed weaker inhibition, with an IC(50) of approximately 35 microM.

Exploring sponge-derived terpenoids for their potency and selectivity against 12-human, 15-human, and 15-soybean lipoxygenases.

Abstract: To sharpen the search for new lipoxygenase inhibitors, we designed a screen to probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15-human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC50 value data obtained provided new insights about structure−activity relationships (SAR) for redox and nonredox inhibitors. All of the compounds tested were isolated from sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known terpenoids. Potent compounds were defined as those having IC50 values < 1 μM, and selectivity was assessed from the three possible IC50 value ratios. One of the four terpenoid redox inhibitors studied, puupehenone (2), was equivalent to or better in potency than the well-known redox inhibitor nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited notable selectivity. Th...