Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors. Discovery of A-289099 as an orally active antitumor agent.
A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.
Li
Qun
Q
Cancer Research, Abbott Laboratories, 60064-6101, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
Woods
Keith W
KW
Claiborne
Akiyo
A
Gwaltney
Stephen L
SL
Barr
Kenneth J
KJ
Liu
Gang
G
Gehrke
Laura
L
Credo
R Bruce
RB
Hui
Yu Hua
YH
Lee
Jang
J
Warner
Robert B
RB
Kovar
Peter
P
Nukkala
Michael A
MA
Zielinski
Nicolette A
NA
Tahir
Stephen K
SK
Fitzgerald
Michael
M
Kim
Ki H
KH
Marsh
Kennan
K
Frost
David
D
Ng
Shi-Chung
SC
Rosenberg
Saul
S
Sham
Hing L
HL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011108:Polymers / Q000138:chemical synthesis; D051381:Rats; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007211:Indoles; D010080:Oxazoles; D011108:Polymers; D014404:Tubulin; C456410:A 289099