Methylalpinumisoflavone inhibits hypoxia-inducible factor-1 (HIF-1) activation by simultaneously targeting multiple pathways.

Hypoxia is a common feature of solid tumors, and the extent of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective molecular target for anticancer drug discovery directed at tumor hypoxia. A natural product chemistry-based approach was employed to discover small molecule inhibitors of HIF-1.

Strongylophorines: natural product inhibitors of hypoxia-inducible factor-1 transcriptional pathway.

Rapidly increasing experimental and clinical data provides evidence for the role of hypoxia inducible factor-1 (HIF-1) as a crucial mediator of tumor survival and progression. In our effort to identify inhibitors of the HIF-1 activation pathway, we screened fractions from marine invertebrates. Fractions from an extract of Petrosia (Strongylophora) strongylata potently inhibited the HIF-1 activation pathway.

Synthesis and biological evaluation of imidazoquinoxalinones, imidazole analogues of pyrroloiminoquinone marine natural products.

This report describes the synthesis and biological activity of imidazoquinoxalines, benzimidazole-based analogues of indole-based pyrroloiminoquinone marine natural products. Our analogues consist of series 1, which possesses the ethylene tether and extended amidine feature found in the pyrroloiminoquinone natural products, and series 2, which also has the ethylene tether but with an electrostatically stabilized iminoquinone rather than a resonance stabilized iminoquinone (i.e.

Theopapuamide, a cyclic depsipeptide from a Papua New Guinea lithistid sponge Theonella swinhoei.

Theopapuamide (1), a new cytotoxic peptide, has been isolated from the lithistid sponge Theonella swinhoei from Papua New Guinea. The structure was established by analysis of NMR, mass spectrometry, and chemical methods. The undecapeptide (1) contains several unusual amino acid residues, of which the occurrence of beta-methoxyasparagine and 4-amino-5-methyl-2,3,5-trihydroxyhexanoic acid (Amtha) is unprecedented in natural peptides.

Terpenoid tetrahydroisoquinoline alkaloids emetine, klugine, and isocephaeline inhibit the activation of hypoxia-inducible factor-1 in breast tumor cells.

Klugine (1), isocephaeline (2), and emetine (4) inhibited hypoxia-inducible factor-1 (HIF-1) activation by hypoxia in T47D breast tumor cells (IC(50) values 0.2, 1.1, and 0.

Saururus cernuus lignans--potent small molecule inhibitors of hypoxia-inducible factor-1.

Hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective therapeutic target for solid tumors. In search of novel small molecule HIF-1 inhibitors, 5400 natural product-rich extracts from plants, marine organisms, and microbes were examined for HIF-1 inhibitory activities using a cell-based reporter assay. Bioassay-guided fractionation and isolation, followed by structure elucidation, yielded three potent natural product-derived HIF-1 inhibitors and two structurally related inactive compounds.

Laurenditerpenol, a new diterpene from the tropical marine alga Laurenciaintricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells.

The degree of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) promotes tumor cell adaptation and survival under hypoxic conditions. Therefore, specific HIF-1 inhibitors represent an important new class of potential tumor-selective therapeutic agents.

Mechanism targeted discovery of antitumor marine natural products.

Antitumor drug discovery programs aim to identify chemical entities for use in the treatment of cancer. Many strategies have been used to achieve this objective. Natural products have always played a major role in anticancer medicine and the unique metabolites produced by marine organisms have increasingly become major players in antitumor drug discovery.

Reversal of fluconazole resistance in multidrug efflux-resistant fungi by the Dysidea arenaria sponge sterol 9alpha,11alpha-epoxycholest-7-ene-3beta,5alpha,6alpha,19-tetrol 6-acetate.

The sponge sterol 9alpha,11alpha-epoxycholest-7-ene-3beta,5alpha,6alpha,19-tetrol 6-acetate (ECTA) (1) is the first marine natural product to reverse fluconazole resistance mediated by a Candida albicans MDR efflux pump. The IC(50) of fluconazole is decreased from 300 to 8.5 microM (35-fold enhancement) when combined with 1(3.