Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anti-Cancer Therapy.

This study explores the anti-cancer potential of N-methylated open-ring derivatives of carborane-substituted diclofenac analogs. By N-methylation, the open-chain form could be trapped and cyclization back to lactam or amidine derivatives was inhibited. A small library of carborane- and phenyl-based secondary and tertiary arylamines bearing carboxylic acid or nitrile groups was synthesized and analyzed for their COX-affinity in vitro and in silico. The compounds were further evaluated against mouse adenocarcinoma (MC38), human colorectal carcinoma (HCT116) and human colorectal adenocarcinoma (HT29) cell lines and showed potent cytotoxicity. Additional biological assessments of the mode of action were performed using flow cytometric techniques and fluorescence microscopy. The data obtained revealed a common antiproliferative effect coupled with the induction of caspase-independent apoptosis and the specific effects of the compound on the phenotype of MC38 cells, resulting in impaired cell viability of MC38 cells and satisfactory selectivity exceeding the antitumor activity of diclofenac.