Discovery and mechanistic insights into thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines inhibitors targeting tubulin for cancer therapy.

Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE

Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]

Pyrimidines*/pharmacology ; Pyrimidines*/chemistry ; Pyrimidines*/chemical synthesis ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Cell Proliferation*/drug effects ; Tubulin*/metabolism ; Drug Screening Assays, Antitumor* ; Tubulin Modulators*/pharmacology ; Tubulin Modulators*/chemistry ; Tubulin Modulators*/chemical synthesis; Humans ; Structure-Activity Relationship ; Molecular Structure ; Apoptosis/drug effects ; Dose-Response Relationship, Drug ; Cell Line, Tumor ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/pharmacology ; Heterocyclic Compounds/chemical synthesis ; Drug Discovery ; Models, Molecular

Guided by the X-ray cocrystal structure of the lead compound 4a, we developed a series of thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines demonstrating potent antiproliferative activity against four tumor cell lines. Two analogs, 13 and 25d, exhibited IC 50 values around 1 nM and overcame P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). At low concentrations, 13 and 25d inhibited both the colony formation of SKOV3 cells in vitro and tubulin polymerization. Furthermore, mechanistic studies showed that 13 and 25d induced G 2 /M phase arrest and apoptosis in SKOV3 cells, as well as dose-dependent inhibition of tumor cell migration and invasion at low concentrations. Most notably, the X-ray cocrystal structures of compounds 4a, 25a, and the optimal molecule 13 in complex with tubulin were elucidated. This study identifies thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines as representatives of colchicine-binding site inhibitors (CBSIs) with potent antiproliferative activity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Keywords: Colchicine-binding site inhibitors; Crystal structure; Thieno[3,2-d]pyrimidine; Tubulin

0 (Pyrimidines)
0 (Antineoplastic Agents)
0 (Tubulin)
0 (Tubulin Modulators)
0 (Heterocyclic Compounds)

Date Created: 20240707 Date Completed: 20240809 Latest Revision: 20240814

20240815

10.1016/j.ejmech.2024.116649

38972078