Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α‐ and β‐tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β‐tubulin have been reported. Nocodazole (NZ) and colch...

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Published in:ChemMedChem 2020-10, Vol.15 (19), p.1802-1812
Main Authors: Herrera‐Vázquez, Frida S., Matadamas‐Martínez, Félix, Aguayo‐Ortiz, Rodrigo, Dominguez, Laura, Ramírez‐Apan, Teresa, Yépez‐Mulia, Lilián, Hernández‐Luis, Francisco
Format: Article
Language:English
Subjects:
Antineoplastic drugs
antiproliferative activity
Antitumor agents
Binding sites
Biotechnology
Colchicine
Depolymerization
Derivatives
diaminoquinazoline
Drug development
Immunofluorescence
Leukocytes (mononuclear)
Microtubules
Molecular docking
Molecular dynamics
Nocodazole
nocodazole site
Peripheral blood mononuclear cells
Polymerization
Polymers
Tubulin
tubulin polymerization inhibition
Tumor cell lines
Western blotting
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Summary:Microtubules are highly dynamic polymers composed of α‐ and β‐tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β‐tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well‐known tubulin‐depolymerizing agents that have close binding sites in the β‐tubulin. In this study, we designed and synthesized a set of nine 2,4‐diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC‐3, HCT‐15, MCF‐7, MDA‐MB‐231, and SK‐LU‐1), a noncancerous one (COS‐7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK‐LU‐1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non‐N‐substituted 2,4‐diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization. More is not always better: A set of nine 2,4‐diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4‐diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000185