ABSTRACT
Two new cyclic depsipeptides named swinhopeptolides A (1) and B (2) have been isolated from the marine sponge Theonella swinhoei cf. verrucosa, collected from Papua New Guinea. They each contain 11 diverse amino acid residues and 13-carbon polyketide moieties attached at the N-terminus. Compounds 1 and 2 each exist as two conformers in DMSO-d6 due to cis/trans isomerism of the proline residue, and their structures were successfully assigned by extensive NMR analyses complemented by chemical degradation and derivatization studies. Swinhopeptolide B (2) contains a previously undescribed 2,6,8-trimethyldeca-(2E,4E,6E)-trienoic acid moiety N-linked to a terminal serine residue. Swinhopeptolides A (1) and B (2) showed significant inhibition of the Ras/Raf signaling pathway with IC50 values of 5.8 and 8.5 µM, respectively.
Subject(s)
Depsipeptides/pharmacology , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Theonella/chemistry , ras Proteins/antagonists & inhibitors , Amino Acids/chemistry , Animals , Depsipeptides/chemistry , Depsipeptides/isolation & purification , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Papua New Guinea , Porifera/chemistry , Proto-Oncogene Proteins c-raf/metabolism , Signal Transduction/drug effects , ras Proteins/metabolismABSTRACT
A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68â¯427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts.
Subject(s)
Astrocytoma/drug therapy , Biological Products/isolation & purification , Biological Products/pharmacology , Fabaceae/chemistry , Millettia/chemistry , Rotenone/analogs & derivatives , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Biological Products/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Humans , Mice , Molecular Structure , Rotenone/chemistry , Rotenone/isolation & purification , Rotenone/pharmacologyABSTRACT
Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 microM.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Macrolides/chemistry , Macrolides/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Porifera/chemistry , Animals , Antineoplastic Agents/isolation & purification , Drug Screening Assays, Antitumor , Humans , Macrolides/isolation & purification , Models, Molecular , Molecular Structure , Neoplasms/drug therapy , Organophosphorus Compounds/isolation & purification , Oxazoles/isolation & purification , Papua New GuineaABSTRACT
Five new naphthopyrones (1-5) along with the known compounds TMC-256A1, 5,8-dihydroxy-6-methoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one, TMC-256C1, comaparvin, 6-methoxycomaparvin, and 6-methoxycomaparvin 5-methyl ether (6-11) were isolated from crinoids of the family Comasteridae. All compounds were tested for their ability to inhibit the multidrug transporter ABCG2, which plays a role in drug resistance. Six of the seven angular naphthopyrones showed moderate activity with <60% inhibition of ABCG2-mediated transport as compared to the positive control fumitremorgin C. None of the linear naphthopyrones inhibited ABCG2-mediated efflux.
