Novel derivatives of 1,3,4-oxadiazoles are potent mitostatic agents featuring strong microtubule depolymerizing activity in the sea urchin embryo and cell culture assays.
A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site.
Kiselyov
Alex S
AS
deCODE Chemistry, 2501 Davey Road, Woodridge, Chicago, IL 60616, USA. akiselyov@decode.com
Semenova
Marina N
MN
Chernyshova
Natalya B
NB
Leitao
Andrei
A
Samet
Alexandr V
AV
Kislyi
Konstantine A
KA
Raihstat
Mikhail M
MM
Oprea
Tudor
T
Lemcke
Heiko
H
Lantow
Margaréta
M
Weiss
Dieter G
DG
Ikizalp
Nazli N
NN
Kuznetsov
Sergei A
SA
Semenov
Victor V
VV
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010641:Phenotype; D012617:Sea Urchins / Q000187:drug effects* / Q000196:embryology* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010069:Oxadiazoles