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

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 Научная публикация

Журнал

European Journal of Medicinal Chemistry
ISSN: 1768-3254 , E-ISSN: 0223-5234

Вых. Данные

Год: 2010, Том: 45, Номер: 5, Страницы: 1683-1697 Страниц : 15 DOI: 10.1016/j.ejmech.2009.12.072

Авторы

Kiselyov Alex S. ¹ , Semenova Marina N. ² , Chernyshova Natalya B. ³ , Leitao Andrei ⁴ , Samet Alexandr V. ³ , Kislyi Konstantine A. ³ , Raihstat Mikhail M. ³ , Oprea Tudor ⁴ , Lemcke Heiko ⁵ , Lantow Margaréta ⁵ , Weiss Dieter G. ⁵ , Ikizalp Nazli N. ⁶ , Kuznetsov Sergei A. ⁵ , Semenov Victor V. ^6,3

Организации

1	deCODE Chemistry, 2501 Davey Road, Woodridge, Chicago, IL 60616, USA
2	Institute of Developmental Biology, RAS 26 Vavilov Str., Moscow 119334, Russia
3	Zelinsky Institute of Organic Chemistry, RAS 47 Leninsky Prospect, Moscow 117913, Russia
4	Department of Biocomputing, University of New Mexico, Albuquerque, NM, USA
5	Institute of Biological Sciences University of Rostock, 3 Albert-Einstein-Str., D-18059 Rostock, Germany
6	Chemical Block Ltd., 3 Kyriacou Matsi, Limassol 3723, Cyprus

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 A.S. , Semenova M.N. , Chernyshova N.B. , Leitao A. , Samet A.V. , Kislyi K.A. , Raihstat M.M. , Oprea T. , Lemcke H. , Lantow M. , Weiss D.G. , Ikizalp N.N. , Kuznetsov S.A. , Semenov V.V.
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
European Journal of Medicinal Chemistry. 2010. V.45. N5. P.1683-1697. DOI: 10.1016/j.ejmech.2009.12.072 WOS Scopus OpenAlex

Web of science:	WOS:000276695200001
Scopus:	2-s2.0-77949492506
OpenAlex:	W2032104847

БД	Цитирований
OpenAlex	78
Scopus	89
Web of science	85