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

Abstract

Microtubules are highly dynamic polymers composed of αand 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.

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations

“…Paclitaxel ( PTX ) was included as a positive control since this compound stabilizes microtubules in the growth phase. The V max value of 47.0 mOD/min indicates the absence of the nucleation phase and rapid growth, consistent with previous experiments . Conversely, NZ inhibits the growth phase ( V max = 6.0 mOD/min), leading to a V max 3.5 times lower than that of the control.…”

“…Although the replacement of naphthyl with quinoline resulted in a decrease in the binding free energy, the incorporation of chlorine at position 5 ( 5d ) or methyl at position 2 ( 5e ) in this heterocycle showed an improvement in the affinity. Compound 5d was incorporated to the perturbation map since in a recent work we found that a quinazoline derivative comprising the 5-chloroquinoline substituent exhibited the best antiproliferative activity against the SK-LU-1 cell line (IC 50 = 5.0 ± 0.2 μM) and inhibited the tubulin polymerization rate in a concentration-dependent manner . In the same study, we suggested that the 5-chloroquinoline substituent was positioned toward the COL pocket, resulting in an increased number of hydrophobic interactions.…”

An Updated Overview on the Synthesis and Anticancer Evaluation of Quinazoline Derivatives

“…[31] Hernandez-Luiz and his team synthesized a series of novel 2,4-diaminoquinazoline derivatives and evaluated their anticancer activity against five cancer cell lines, namely PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1. [32] Among them, compounds 1 (bearing 3-Chlorophenoxy) and 2 (bearing 5chloroquinolin-8-yl) showed promising anti-proliferative activity by inhibiting tubulin polymerization. At 10 μM concentration, compound 1 exhibited a tubulin polymerization curve similar to that of nocodazole.…”

Microtubules as a target of antitumor drugs

“…синтезированные производные 2,4-диаминохиназолина проявляют антипролиферативную активность, ингибируя полимеризацию тубулина. [31].…”