Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents Full article

Journal

ACS Combinatorial Science
ISSN: 2156-8952 , E-ISSN: 2156-8944

Output data

Year: 2018, Volume: 20, Number: 12, Pages: 700-721 Pages count : 22 DOI: 10.1021/acscombsci.8b00113

Authors

Semenova Marina N ¹ , Demchuk Dmitry V ² , Tsyganov Dmitry V ² , Chernysheva Natalia B ² , Samet Alexander V ² , Silyanova Eugenia A ² , Kislyi Victor P ² , Maksimenko Anna S ² , Varakutin Alexander E ² , Konyushkin Leonid D ² , Raihstat Mikhail M ² , Kiselyov Alex S ³ , Semenov Victor V ²

Affiliations

1	N. K. Koltzov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation
2	N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation
3	Genea Biocells US, Inc., Suite 210, 11099 North Torrey Pines Road, La Jolla, California 92037, United States

A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure–activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure–activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.

Semenova M.N. , Demchuk D.V. , Tsyganov D.V. , Chernysheva N.B. , Samet A.V. , Silyanova E.A. , Kislyi V.P. , Maksimenko A.S. , Varakutin A.E. , Konyushkin L.D. , Raihstat M.M. , Kiselyov A.S. , Semenov V.V.
Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents
ACS Combinatorial Science. 2018. V.20. N12. P.700-721. DOI: 10.1021/acscombsci.8b00113 WOS Scopus OpenAlex

Web of science:	WOS:000453108700003
Scopus:	2-s2.0-85058101766
OpenAlex:	W2901274127

DB	Citing
OpenAlex	62
Scopus	60
Web of science	57