Design, Synthesis and Evaluation of 2, 4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors. (26th August 2020)

• Record Type: Journal Article
• Authors: Herrera‐Vázquez, Frida S.; Matadamas‐Martínez, Félix; Aguayo‐Ortiz, Rodrigo; Dominguez, Laura; Ramírez‐Apan, Teresa; Yépez‐Mulia, Lilián; Hernández‐Luis, Francisco
• Is Part Of: ChemMedChem. Volume 15:Number 19(2020)
• Page Start: 1802
• Page End: 1812
• Publication Date: 2020-08-26
• Subjects: antiproliferative activity -- diaminoquinazoline -- molecular dynamics -- nocodazole site -- tubulin polymerization inhibition; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000185
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : 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.