New manzamine alkaloids with activity against infectious and tropical parasitic diseases from an Indonesian sponge

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.     

Kinetic studies and bioactivity of potential manzamine prodrugs

The manzamines represent a class of marine natural products that show considerable promise in the control of malaria but generate GI distress in rodents when administered orally in high doses. In an effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity, we prepared acetylated 8-hydroxymanzamine A analogues including 8-acetoxymanzamine A (3) and 8,12-diacetoxymanzamine A (4), and 8-methoxymanzamine A (5) beginning with 8-hydroxymanzamine A (2). The semisynthetic analogues were assayed for antimalarial and antimicrobial activities, cytotoxicity, and biological and chemical stability. Due to gradual hydrolysis of the ester group, application of monoacetate 3 as an antimalarial prodrug was investigated. The in vitro and in vivo bioassays show that acetylated analogues exhibit significant antimalarial activity (IC50( 3) 9.6-30 ng/mL), which are comparable to the parent molecule; however the monoaceate 3 was shown to actually produce higher toxicity at 30 mg/kg when administered orally.     

Manzamine B and E and ircinal A related alkaloids from an Indonesian Acanthostrongylophora sponge and their activity against infectious, tropical parasitic, and Alzheimer's diseases

Four new manzamine-type alkaloids, 12,28-oxamanzamine E (2), 12,34-oxa-6-hydroxymanzamine E (3), 8-hydroxymanzamine B (5), and 12,28-oxaircinal A (11), were isolated from three collections of an Indonesian sponge of the genus Acanthostrongylophora together with 13 known manzamine alkaloids, ircinal A, ircinol A, xestomanzamine A, manzamines A, E, F, J, and Y, manadomanzamines A and B, neo-kauluamine, 8-hydroxymanzamine A, and manzamine A N-oxide. The structures of the new compounds were elucidated by means of 1D and 2D NMR spectroscopic methods. Three of these compounds (2, 3, and 11) possess a unique manzamine-type aminal ring system generated through an ether linkage between carbons 12-28 or between carbons 12-34. In the case of manzamine B and related metabolites, carbons 11 and 12 of the typical manzamine structure have an epoxide group and add to our growing understanding of manzamine structure-activity relationships (SAR) and metabolism. The bioactivity and SAR for a number of previously reported manzamine-related metabolites against malaria, leishmania, tuberculosis, and HIV-1 are also presented. Manzamine Y (9) showed significant inhibitory activity of GSK3, an enzyme implicated in Alzheimer's disease pathology. The toxicity of manzamine A and neo-kauluamine was evaluated against both medaka fry and eggs.     

Three new manzamine alkaloids from a common Indonesian sponge and their activity against infectious and tropical parasitic diseases

Three new manzamine-type alkaloids, 12,34-oxamanzamine E (3), 8-hydroxymanzamine J (4), and 6-hydroxymanzamine E (8), as well as 12 previously characterized manzamine alkaloids have been isolated from a common Indonesian sponge of the genus Acanthostrongylophora. The structures of the new compounds have been established on the basis of 1D and 2D NMR spectroscopic analysis and comparison of the data to literature values of related compounds. The biological activities and structure-activity relationship of the manzamines against malaria, Mycobacterium tuberculosis, Leishmania, HIV-1, and AIDS opportunistic infections are discussed. A plausible pathway for the formation of the 12,34-oxaether bridge in compound 3 is also provided.     

Antineoplastic agents. 536. New sources of naturally occurring cancer cell growth inhibitors from marine organisms, terrestrial plants, and microorganisms(1a,)

Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.     

Phytochemical studies on Stemona aphylla: isolation of a new stemofoline alkaloid and six new stemofurans

A new stemofoline alkaloid, (2'S)-hydroxy-(11S,12R)-dihydrostemofoline (3), new stemofurans M-R (8-13), and known compounds stemofoline (1), (2'S)-hydroxystemofoline (2), stemofuran E (4), stemofuran F (5), stemofuran J (6), and stilbostemin F (7) have been isolated from the root extracts of Stemona aphylla. The structures and relative configurations of these new compounds have been determined by spectroscopic data interpretation and from semisynthetic studies. These natural and semisynthetic alkaloids were tested for acetylcholinesterase inhibitory activities and were found to be 10-20 times less active than 1',2'-didehydrostemofoline itself. Stemofurans 4, 6, 8, 11, and 13 were tested for their antibacterial and antifungal activities. Three of these showed antibacterial activities against MRSA with MIC values of 15.6 μg/mL.     

Transformations of manool. tri- and tetracyclic norditerpenoids with in vitro activity against Plasmodium falciparum

The known 17-norisopimar-15-ene-8beta,13beta-diol (5) and five new semisynthetic norditerpenoids, ethyl 17-norabiet-13(15)-E-en-8beta-ol-16-oate (6), ethyl 17-norabiet-13(15)-Z-en-8beta-ol-16-oate (7), 17-norpimaran-13alpha-ethoxy-8,16-olactone (8), 17-norisopimarane-8beta,15-diol (9), and 17-norarabiet-13(15)-ene-8beta,16-diol (10), were prepared from manool (11). Standard spectroscopic data including X-ray crystal analysis were used to determine the structures of 5-10. All five compounds exhibited in vitro antiplasmodial activity against the malarial parasite Plasmodium falciparum at varying microg mL(-1) concentrations.     

Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease

Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.     

New tirucallane-type triterpenes from Dysoxylum variabile.

Eight new tirucallane-type triterpenes, dyvariabilins A-H (1-8), three known tirucallanes, niloticin (9), dihydroniloticin (10), and tirucalla-7,24-diene-3 beta,23-diol (11), and two known sesquiterpenes, 1-(1-hydroxy-2-methylpropyl)-3a-methyl-7-methyleneoctahydroinden-4-ol and (+)-aphanamol I, were isolated from the stem bark of Dysoxylum variabile. Tirucallanes 1 and 11 with an allylic hydroxy group in the side chain and dyvariabilin C (3) with an alpha-epoxy group at positions 7 and 8 showed high instability in acidic medium and formed five hitherto unknown semisynthetic tirucallanes. Dyvariabilins B (2) and C (3) as well as the mixtures of dyvariabilins E and F (5 and 6) and dyvariabilins G and H (7 and 8) showed weak cytotoxicity against KB cells.     

Semisynthesis of rosmanol and its derivatives. Easy access to abietatriene diterpenes isolated from the genus Salvia with biological activities

The known diterpenes rosmanol (3), rosmaquinone (4), 7-methoxyrosmanol (5), 7-ethoxyrosmanol (6), galdosol (7), and epirosmanol (8) have been obtained by partial synthesis from carnosol (2), an abundant natural product present in Salvia species. The physical and spectroscopic data of these semisynthetic diterpenes were identical to those of authentic natural samples and with data reported in the literature. These abietane diterpenes have very interesting biological activities and are present in the genus Salviain low quantities; thus, the semisynthetic approach described here represents an efficient alternative method to obtain these compounds. Additionally, the known diterpene 16-hydroxyrosmanol (10) and a new aromatic diterpene 11 were obtained from 16-hydroxycarnosol (9) by reaction with Ph3P/NBS in CH2Cl2. The structure of the new compound 11 was established from its spectroscopic data as 12,16-epoxycarnosol.     

Sulfur-containing spiroketal glycosides from Breynia fruticosa

Phytochemical investigation of the chemical constituents of the aerial parts of Breynia fruticosa afforded 10 sulfur-containing spiroketal glycosides, including eight new compounds (1-8) and two known compounds, epibreynin B (9) and breynin B (10). Epibreynin B (9) was previously reported as a semisynthetic oxidation product of breynin A and is now reported from a natural source for the first time. The structures of 1-10 were determined on the basis of spectroscopic and chemical methods.     

Bioactive natural and semisynthetic latrunculins

Marine-derived macrolides latrunculins A and B, of the Red Sea sponge Negombata magnifica, are the first marine natural products that have been found to reversibly bind to actin monomers and to disrupt its organization. Latrunculins are structurally related to many antimicrobial and antiangiogenic macrolides. Several grams of latrunculin B (1), together with a new latrunculin named latrunculin T (2), were isolated from a recent collection of N. magnifica. Semisynthetic modifications of 1, including acetylation, acetalization, and N-hydroxymethylation, afforded four new (4, 5, 7, 8) and two known (6 and 9) semisynthetic analogues. Specifically, 15-O-methyllatrunculin B (6) showed a promising antiangiogenic activity in a chick chorioallantoic membrane assay and antimigratory activity in Boyden's chamber assay. Moreover, latrunculin B (1) and the new N-acetyllatrunculin B (4) displayed potent antimigratory activity in a wound-healing assay. Natural and semisynthetic latrunculins showed potent antimicrobial activity against Candida albicans, Saccharomyces cerevisiae, Staphylococcus aureus, and Bacillus cereus. Latrunculins are potential leads that can be developed as anticancer and antimicrobial agents.     

Inhibitory effects of bufadienolides on interleukin-6 in MH-60 cells

Derivatives of bufogenin isolated from the skin of the Chinese toad, Bufo bufo gargarizans Cantor ("Ch'an Su"), and several semisynthetic derivatives of 20beta,21beta-epoxy-resibufogenin (13) have been evaluated for interleukin-6 (IL-6) antagonistic activity due to their growth-inhibitory activities on IL-6-dependent MH-60 cells. Among the naturally derived compounds (1-17), 20S,21-epoxy-resibufogenin formate (1) showed potent inhibitory activity on the IL-6-dependent growth of MH-60 cells. Epoxide groups at both the C-14, C-15 and C-20, C-21 positions are required to exhibit this type of activity. Compounds acetylated at the C-16 position (7 and 9-11) showed a loss of activity. An oxo group at the C-3 position (8, 14, and 15) resulted in cytotoxicity for both cell lines. Stereochemistry is important for selectivity on suppression of IL-6 activity. Among the semisynthetic derivatives (18-25) of 13, compound 19, with an acetyl group introduced at the C-3 position in comparison to 13, demonstrated considerable growth inhibition of IL-6-dependent MH-60 cells.     

Phytochemical studies on Stemona plants: isolation of stemofoline alkaloids

Six new stemofoline alkaloids, (2'R)-hydroxystemofoline (5), (3'R)-stemofolenol (6), (3'S)-stemofolenol (7), 1',2'-didehydrostemofoline-N-oxide (8), the first C(19) stemofoline alkaloid, methylstemofoline (9), and the first glycosidated Stemona alkaloid, stemofolinoside (10), and three known alkaloids, (2'S)-hydroxystemofoline (2), (11Z)-1',2'-didehydrostemofoline (3), and (11E)-1',2'-didehydrostemofoline (4), have been isolated from a root extract of an unidentified Stemona species. The structure and relative configuration of these new alkaloids have been determined by spectral data interpretation and from semisynthetic studies.     

Potential anticancer activity of naturally occurring and semisynthetic derivatives of aculeatins A and B from Amomum aculeatum

Activity-guided fractionation of hexanes- and CHCl 3-soluble extracts of Amomum aculeatum leaves, collected in Indonesia, led to the isolation of three new dioxadispiroketal-type ( 3- 5) and two new oxaspiroketal-type ( 6 and 7) derivatives. Nine semisynthetic derivatives ( 1a- 1h and 2a) of the parent compounds, aculeatins A ( 1) and B ( 2), were prepared. All isolates and semisynthetic compounds were tested against a small panel of human cell lines. Of these, aculeatin A ( 1; ED 50 0.2-1.0 microM) was found to be among the most cytotoxic of the compounds tested and was further evaluated in an in vivo hollow fiber assay; it was found to be active against MCF-7 (human breast cancer) cells implanted intraperitoneally at doses of 6.25, 12.5, 25, and 50 mg/kg. However, when 1 was tested using P388 lymphocytic leukemia and human A2780 ovarian carcinoma in vivo models, it was deemed to be inactive at the doses used.     

Semisynthetic analogues of the microtubule-stabilizing agent discodermolide: preparation and biological activity

A series of 12 semisynthetic discodermolide analogues, 2-13, have been prepared using natural (+)-discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described.     

Pyrrolizidine alkaloids from Cynoglossum creticum. Synthesis of the pyrrolizidine alkaloids echinatine, rinderine, and analogues

Reinvestigation of Cynoglossum creticum led to the isolation of the previously reported echinatine [1] and heliosupine [2] as well as rinderine [3], 7-angelylheliotridine [4] and a new alkaloid, cynoglossamine [5]. The structures have been determined by spectral means (ir, ms, 1H-13C HETCOR nmr), comparison with literature data and authentic samples, and/or syntheses. In addition, 1 and all three of its isomers 3, 6, and 7 and other semisynthetic analogues (8-13) were prepared and characterized.     

C-5-substituted antifeedant silphinene sesquiterpenes from Senecio palmensis

The new sesquiterpenes, 5alpha-senecioyloxysilphinen-3-one (5), 5alpha-tigloyloxysilphinen-3-one (7), and 3beta-hydroxy-5alpha-angeloyloxysilphinene (8), and the known compounds (6S)-2,10-bisaboladien-1-one (1), 6,7-epoxy-3(15)-caryophyllene (2), 6,7-epoxy-2,9-humuladiene (3), 5alpha-angeloyloxysilphinen-3-one (4), and 5alpha-acetoxysilphinen-3-one (6) were isolated from bioactive fractions of Senecio palmensis. The structures of these compounds were established by spectroscopic analysis and chemical evidence. The semisynthetic analogues silphinen-3,5-dione (9), 5alpha-hydroxysilphinen-3-one (10), 5beta-hydroxysilphinen-3-one (11), 5beta-acetoxysilphinen-3-one (12), and 5beta-isobutyryloxysilphinen-3-one (13) were generated to carry out a structure-activity study on the antifeedant action of these molecules against several divergent insect species.     

Inhibitory effects of diterpenoid alkaloids on the growth of A172 human malignant cells

The cytotoxicity against A172 human malignant glioma cells was examined for 14 alkaloids from the roots of Aconitum yesoense var. macroyesoense and of Aconitum japonicum and from the seeds of Delphinium elatum as well as for 25 semisynthetic derivatives. The major alkaloid constituents of A. yesoense var. macroyesoense, kobusine (2) and pseudokobusine (3), a minor alkaloid constituent of A. japonicum, aljesaconitine A (5), and six alkaloid derivatives, N-deethyldelcosine (10), N-deethyldelsoline (11), 12-benzoylluciculine (18), 12-anisoylluciculine (19), 6,11-dibenzoylpseudokobusine (28), and 6-veratroylpseudokobusine (29), had only very weak activity. Four acylated alkaloid derivatives, 12-acetylluciculine (23), 11-veratroylpseudokobusine (30), 11-(m-trifluoromethylbenzoyl)pseudokobusine (32), and 11-(m-trifluoromethylbenzoyl)kobusine (39), exhibited more potent activity, while pseudokobusine 11-cinnamoate (31), 11-anisoate (33), and 11-p-nitrobenzoate (34) were found to be the most potent cytotoxic agents.     

Veraguamides A-G, cyclic hexadepsipeptides from a dolastatin 16-producing cyanobacterium Symploca cf. hydnoides from Guam

Cytotoxicity-directed purification of a Symploca cf. hydnoides sample from Cetti Bay, Guam, afforded seven new cyclic depsipeptides, veraguamides A-G (1-7), together with the known compound dolastatin 16. The planar structures of 1-7 were elucidated using NMR and MS experiments, while enantioselective HPLC and Mosher's analysis of acid and base hydrolysates, respectively, were utilized to assign the absolute configurations of the stereocenters. Veraguamides A-G (1-7) are characterized by the presence of an invariant proline residue, multiple N-methylated amino acids, an α-hydroxy acid, and a C8-polyketide-derived β-hydroxy acid moiety with a characteristic terminus as either an alkynyl bromide, alkyne, or vinyl group. These compounds and a semisynthetic analogue (8) showed moderate to weak cytotoxic activity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Preliminary structure-activity relationship analysis identified several sensitive positions in the veraguamide scaffold that affect the cytotoxic activity of this compound class. Dolastatin 16 showed only weak cytotoxic activity on both cell lines tested. The complete stereostructure of dolastatin 16 was proposed for the first time through degradation followed by a combination of advanced Marfey's analysis and modified Mosher's analysis using phenylglycine methyl ester as a chiral anisotropic reagent.