Structure-activity relationships of diverse Annonaceous acetogenins against multidrug resistant human mammary adenocarcinoma (MCF-7/Adr) cells.
Fourteen structurally diverse Annonaceous acetogenins, representing the three main classes of bis-adjacent, bis-nonadjacent, and single-THF ring(s), were tested for their ability to inhibit the growth of adriamycin resistant human mammary adenocarcinoma (MCF-7/Adr) cells. This cell line is resistant to treatment with adriamycin, vincristine, and vinblastine and is, thus, multidrug resistant (MDR). Among a series of bis-adjacent THF ring acetogenins, those with the stereochemistry of threo-trans-threo-trans-erythro (from C-15 to C-24) were the most potent with as much as 250 times the potency of adriamycin. A spacing of 13 carbons between the flanking hydroxyl of the THF ring system and the gamma-unsaturated lactone seems to be optimum with a spacing of 11 and 9 carbons being significantly less active. Several single-THF ring compounds were also quite potent with gigantetrocin A (11) being the most potent compound tested. The acetogenins may, thus, have chemotherapeutic potential, especially with regard to MDR tumors.
Oberlies
N H
NH
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907-1333, USA.
Chang
C J
CJ
McLaughlin
J L
JL
D000230:Adenocarcinoma; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; C061022:bullatacin