Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors

Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors Full article

Journal

RSC Medicinal Chemistry
ISSN: 2632-8682

Output data

Year: 2025, Volume: 16, Pages: 274-285 Pages count : 12 DOI: 10.1039/d4md00541d

Authors

Anisimov Mikhail N. ^1,2 , Boichenko Maksim A. ³ , Shorokhov Vitaly V. ³ , Borzunova Julia N. ² , Janibekova Marina ⁴ , Mustyatsa Vadim V. ^1,4 , Lifshits Ilya A. ² , Plodukhin Andrey Yu. ³ , Andreev Ivan A. ⁵ , Ratmanova Nina K. ⁵ , Zhokhov Sergey S. ³ , Tarasenko Elena A. ³ , Ipatova Daria A. ³ , Pisarev Alexander R. ⁶ , Vorobjev Ivan A. ^7,8,4 , Trushkov Igor V. ⁹ , Ivanova Olga A. ³ , Gudimchuk Nikita B. ^1,2

Affiliations

1	Center for theoretical problems of physicochemical pharmacology, Moscow, 109029, Russia
2	Department of Physics, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia
3	Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia
4	National Laboratory Astana, Astana, 010000, Kazakhstan
5	Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia
6	Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow 117418, Russia
7	Department of Biology, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia
8	Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
9	N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russia

Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinoline-1(2H)-ones 3 as inhibitors of tubulin polymerization. We evaluated their effects on microtubule dynamics in vitro and on the proliferation of A549 cells, using flow cytometry-based cell cycle analysis. The results were verified with phase-contrast microscopy in three cancer cell lines: A549, HeLa and MCF-7. Guided by molecular modeling of the interactions between tubulin and the most active of the identified compounds, we designed, synthesized, and tested the 3-hydroxyphenyl-substituted compound 3c. This compound was further shown to bind to the colchicine site of tubulin and reduce microtubule growth rates in vitro. Moreover, compound 3c arrested division of the A549 cells in the low micromolar range (IC50 = 5.9 μM) and exhibited cytotoxicity against four different cell lines in the MTT assay for cell proliferation. Our findings demonstrate that 5-aryltetrahydropyrrolo[1,2-a]quinoline-1(2H)-one is a promising scaffold for the development of novel tubulin polymerization inhibitors.

Anisimov M.N. , Boichenko M.A. , Shorokhov V.V. , Borzunova J.N. , Janibekova M. , Mustyatsa V.V. , Lifshits I.A. , Plodukhin A.Y. , Andreev I.A. , Ratmanova N.K. , Zhokhov S.S. , Tarasenko E.A. , Ipatova D.A. , Pisarev A.R. , Vorobjev I.A. , Trushkov I.V. , Ivanova O.A. , Gudimchuk N.B.
Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors
RSC Medicinal Chemistry. 2025. V.16. P.274-285. DOI: 10.1039/d4md00541d WOS OpenAlex

Web of science:	WOS:001340491000001
OpenAlex:	W4403431050

Пока нет цитирований