Results in Chemistry (Jun 2024)
Synthesis, structure analysis, Hirshfeld surface studies, molecular docking studies against cyclin-dependent kinases (CDKs) of sulfonamide decorated N6-benzyl aminopurines for cancer treatment
Abstract
Cyclin-dependent kinases (CDKs) are recognized as the primary regulators of the cell cycle. CDKs are over-expressed in various types of cancer. Inhibiting CDKs with small molecules can reduce tumor growth and benefit cancer patients. In the current study, sulfonamide-decorated N6-benzyl aminopurines such as ligand 1: (α- alpha (Purin-6-ylamino)-p-toluenesulfonamide) and ligand 2: (α-(2-Amino purin-6-ylamino)-p-toluenesulfonamide)) purine were synthesized and explored for their anticancer efficacy. Crystallographic analysis revealed that ligand 1 crystallizes in P-1 of the triclinic and ligand 2 molecule in C2/c or P21/c of the monoclinic systems. Hirshfeld surface and X-ray crystallographic studies discovered that ligand 2 possesses stronger noncovalent interaction ability than roscovitine. In silico analysis showed that ligand 2 had a higher binding affinity for ATP binding sites of CDK1, CDK2, and CDK4 receptors than roscovitine (a known CDK inhibitor). The enhanced binding affinity of ligand 2 with CDKs was found to be associated with strong noncovalent interactions between ligand 2 and specific amino acids in CDKs. Cytotoxicity studies were conducted on the glioblastoma cell line (U251) by incubating cells with ligands 0, 1, and 2, roscovitine, and the established anticancer drug Temozolomide (TMZ). Ligand 2 (66.12 ± 1.09 µM) demonstrated better cytotoxicity compared to ligand 1 (81.22 ± 0.30 µM), roscovitine (127.10 ± 0.47 µM), and TMZ (165.11 ± 1 µM). It was well known that CDK inhibition can lead to cell cycle arrest. Intriguingly, ligand 2 induced G2/M phase cell cycle arrest by increasing the percentage of the G2/M phase cell population from 21.08 % to 47.79 % in U251 cells. Based on these results, ligand 2 showed anticancer properties by binding to the ATP binding site of CDKs. Hence, ligand 2 can serve as a potential lead molecule in the development of effective anticancer agents.
