Synthesis and evaluation of tetrahydropyrrolo[1,2a]quinolin-1(2H)-ones as new 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.Yu. 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.
7 February 2025Royal Society of Chemistry
RSC Medicinal Chemistry
2025#16Issue 1274 - 285 pp.
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.
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Department of Physics, M.V. Lomonosov Moscow State University, Moscow, 119991, Russian Federation
Center for theoretical problems of physicochemical pharmacology, Moscow, 109029, Russian Federation
Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119991, Russian Federation
National Laboratory Astana, Astana, 010000, Kazakhstan
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russian Federation
Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, 117418, Russian Federation
Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Department of Biology, M.V. Lomonosov Moscow State University, Moscow, 119991, Russian Federation
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991, Russian Federation
Department of Physics
Center for theoretical problems of physicochemical pharmacology
Department of Chemistry
National Laboratory Astana
Dmitry Rogachev National Medical Research Center of Pediatric Hematology
Faculty of Biology and Biotechnologies
Department of Biology
Department of Biology
N.D. Zelinsky Institute of Organic Chemistry
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