Synthesis, molecular docking and antiproliferative activity of upper rim modified azo calix[4]arene derivatives

Abstract

Azo derivatives of calixarenes are mostly reported for the extraction of transition metal ions and as switchable receptors or sensors for Na⁺ and K⁺ ions to mimic the biological Na⁺/K⁺ ion pump. Only a few reports describe the drug-like potential of azo calixarenes. The current work is an attempt to explore the anticancer potential of three upper rims modified azo derivatives of calix[4]arene. Sulfaguanidine (SGC), sulfanilamide (SCM), and 4-amino-2-methylbenzoic acid (COX) groups were linked with calix[4]arene via azo linkage and their antiproliferative effect was evaluated against breast (MCF7 and MDA-MB-231), colon (HCT-116), and lung (A549) cancer cell lines using MTT assay. SGC showed antiproliferative effect on MCF7 and MDA-MB-231 breast cancer cells with IC₅₀ values of 32.2 and 27.3 µM, respectively. SCM exerted an antiproliferative activity against MCF7, MDA-MB-231, and HCT-116 cells with IC₅₀ values of 31.8, 50.1, and 28.03 µM, respectively, while COX did not show an antiproliferative effect against all the tested cell lines. The compounds were docked against Cyclin-Dependent Kinase-2 (CDK2) receptor (PDB ID 1FVT) for their possible interactions followed by in vitro analysis by MTT assay. CDK2 was selected as the target enzyme because of the structural similarities of the synthesized compounds with previously reported CDK2 potential inhibitors. The docking results supported the in vitro results for the two compounds. A proposed scheme for using the azo derivatives of calix[4]arene as prodrugs is suggested for further investigation.

Graphical abstract