Molecular-targeted antitumor agents. 15. Neolamellarins from the marine sponge Dendrilla nigra inhibit hypoxia-inducible factor-1 activation and secreted vascular endothelial growth factor production in breast tumor cells.
The transcription factor hypoxia-inducible factor-1 (HIF-1) has emerged as a major antitumor molecular target. Inhibition of HIF-1 activation has been shown to suppress the growth, survival, and metastatic spread of hypoxic tumors. The NCI Open Repository of marine invertebrates and algae lipid extracts was evaluated for HIF-1 inhibitory activity in a T47D human breast tumor cell-based reporter assay. Bioassay-guided chromatographic separation of the active extract from the sponge Dendrilla nigra produced four new lamellarin-like phenolic pyrroles, which most closely resemble the structure of the known D. cactos compound lamellarin O. However, unlike lamellarins, the structures of neolamellarin A (1), neolamellarin B (2), 5-hydroxyneolamellarin B (3), and 7-hydroxyneolamellarin A (4) lack the carboxyl moiety at position C-2 of the substituted pyrrole ring and have a significantly different pattern of oxidation. Compound 4 was found to inhibit hypoxia-induced HIF-1 activation (IC50 1.9 microM) in T47D cells. Hypoxic induction of vascular endothelial growth factor (VEGF), a potent angiogenic factor and HIF-1 target gene, was also inhibited by 4 at the secreted protein level.
Liu
Rui
R
Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677-1848, USA.
Liu
Yang
Y
Zhou
Yu-Dong
YD
Nagle
Dale G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015394:Molecular Structure; D054547:National Cancer Institute (U.S.); D011161:Porifera / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014481:United States; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A