Identification of novel and improved antimitotic agents derived from noscapine.
Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.
Anderson
James T
JT
Athersys, Inc., 3201 Carnegie Avenue, Cleveland, Ohio 44115-2634, USA. janderson@athersys.com
Ting
Anthony E
AE
Boozer
Sherry
S
Brunden
Kurt R
KR
Crumrine
Chris
C
Danzig
Joel
J
Dent
Tom
T
Faga
Laurel
L
Harrington
John J
JJ
Hodnick
William F
WF
Murphy
Steven M
SM
Pawlowski
Gary
G
Perry
Robert
R
Raber
Amy
A
Rundlett
Stephen E
SE
Stricker-Krongrad
Alain
A
Wang
Jianmin
J
Bennani
Youssef L
YL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001704:Biopolymers; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D009665:Noscapine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry
D000970:Antineoplastic Agents; D001704:Biopolymers; D014404:Tubulin; D050257:Tubulin Modulators; D009665:Noscapine