Oxadiazole derivatives as a novel class of antimitotic agents: Synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines.
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Ouyang
Xiaohu
X
Department of Chemistry, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA. shawn_ouyang@yahoo.com
Piatnitski
Evgueni L
EL
Pattaropong
Vatee
V
Chen
Xiaoling
X
He
Hai-Ying
HY
Kiselyov
Alexander S
AS
Velankar
Avdhoot
A
Kawakami
Joel
J
Labelle
Marc
M
Smith
Leon
L
Lohman
Julia
J
Lee
Sui Ping
SP
Malikzay
Asra
A
Fleming
James
J
Gerlak
Jason
J
Wang
Ying
Y
Rosler
Robin L
RL
Zhou
Kai
K
Mitelman
Stan
S
Camara
Margarita
M
Surguladze
David
D
Doody
Jacqueline F
JF
Tuma
M Carolina
MC
D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*
D050256:Antimitotic Agents; D001704:Biopolymers; D010069:Oxadiazoles; D014404:Tubulin