Synthesis and antitumor activity of novel C-7 paclitaxel ethers: discovery of BMS-184476.
The preparation of C-7 paclitaxel ethers is described. Various substituted ethers were prepared via activation of the corresponding methylthiomethyl ether followed by alcohol addition. Variation of the C-7 ether group as well the 3' side chain position led to the discovery of a novel taxane, BMS-184476 (4), with preclinical antitumor activity superior to paclitaxel.
Altstadt
T J
TJ
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O. Box 5100, Wallingford, Connecticut 06492-7660, USA.
Fairchild
C R
CR
Golik
J
J
Johnston
K A
KA
Kadow
J F
JF
Lee
F Y
FY
Long
B H
BH
Rose
W C
WC
Vyas
D M
DM
Wong
H
H
Wu
M J
MJ
Wittman
M D
MD
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004987:Ethers; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004987:Ethers; D043823:Taxoids; C426424:7-methylthiomethylpaclitaxel; D017239:Paclitaxel