Synthesis and structure-activity relationships of nonaromatic taxoids: effects of alkyl and alkenyl ester groups on cytotoxicity.
Several new nonaromatic taxoids are synthesized by means of the beta-lactam synthon method. These include taxoids modified with 3-methylbut-2-enoate, 3-methylbutanoate, and cyclohexanecarboxylate groups in place of the benzoate at the C-2 position. In addition, taxoids with 2-methylprop-1-enyl, 2-methylpropyl, (E)-prop-1-enyl, and cyclohexyl groups at the C-3' position are also prepared in combination with the modifications at C-2. The alkyl and alkenyl ester groups at C-2 displayed pronounced effects on the in vitro cytotoxicity. Two of the fully aliphatic taxoids possess similar or stronger activity than paclitaxel and docetaxel. It is clear that the 2-benzoate does not play a unique role, and replacement with the appropriate alkyl and alkenyl groups provides taxoids with equivalent or superior activity.
Ojima
I
I
Department of Chemistry, State University of New York at Stony Brook 11794-3400, USA.
Kuduk
S D
SD
Pera
P
P
Veith
J M
JM
Bernacki
R J
RJ
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel