Novel cytotoxic 3'-(tert-butyl) 3'-dephenyl analogs of paclitaxel and docetaxel.
3'-(tert-Butyl) 3'-dephenyl analogs of paclitaxel were synthesized from 10-deacetylbaccatin III and oxazolidinecarboxylic acid 7 followed by acylation of intermediate amines 10 and 11. Oxazolidinecarboxylic acid 7 was prepared in five steps and in good overall yield from L-tert-leucine. Twelve analogs were synthesized and evaluated for their in vitro ability to stimulate the formation of microtubules and for their cytotoxicity against B16 melanoma cells. Amide, carbamate, urea, and thiourea congeners were prepared. The most potent derivatives found in this study are the docetaxel analog 13, the N-[(tert-amyloxy)carbonyl] analog 17, and the 3'-phenylurea and 3'-tert-butylurea derivatives 20 and 23. Six of these analogs were shown to be ca. 90 times more soluble in water than paclitaxel and ca. 4-5 times more water-soluble than docetaxel.
Ali
S M
SM
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA.
Hoemann
M Z
MZ
Aubé
J
J
Mitscher
L A
LA
Georg
G I
GI
McCall
R
R
Jayasinghe
L R
LR
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077143:Docetaxel; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D043823:Taxoids; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel