Enantioselective synthesis of saframycin A and evaluation of antitumor activity relative to ecteinascidin/saframycin hybrids.
[formula: see text] A short synthesis of saframycin A is described which begins with a readily available intermediate previously utilized for the total synthesis of ecteinascidin 743. A key step in this synthesis is the use of 1-fluoro-3,5-dichloropyridinium triflate to oxidize a phenolic ring to a 1,4-benzoquinone unit while simultaneously cleaving a methoxymethyl ether of a different phenolic ring to the corresponding phenol (4-->5). The common intermediate (2) for the synthesis of saframycin A (1) and ecteinascidin 743 also allowed the synthesis of two hybrids of these structures (6 and 7). Whole cell bioassays for antitumor activity using lung, colon, melanoma, and prostate-derived tumor cell lines allowed a clear correlation of structure with biological activity in this series.
Martinez
E J
EJ
Harvard University, Department of Chemistry and Chemical Biology, Cambridge, Massachusetts 02138, USA.
Corey
E J
EJ
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D004149:Dioxoles / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; C026925:saframycin A