# Advances in Diclofenac Derivatives: Exploring Carborane‐Substituted N‐Methyl and Nitrile Analogs for Anticancer Therapy

## TL;DR

This study explores new diclofenac derivatives with carborane substitutions that show strong anticancer effects, particularly in mouse and human cancer cell lines.

## Contribution

The novel use of N-methylation to prevent lactam formation in carborane-substituted diclofenac analogs, leading to potent anticancer derivatives.

## Key findings

- Carborane-substituted diclofenac analogs show potent cytotoxicity against MC38, HCT116, and HT29 cancer cell lines.
- The compounds induce caspase-independent apoptosis and exhibit antiproliferative effects.
- N-methylation prevents cyclization and enables open-chain derivatives with improved anticancer activity compared to diclofenac.

## Abstract

This study explores the anticancer 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 is inhibited. A small library of carborane‐ and phenyl‐based secondary and tertiary arylamines bearing carboxylic acid or nitrile groups is synthesized and analyzed for their COX affinity in vitro and in silico. The compounds are further evaluated against mouse adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29) cell lines and show potent cytotoxicity. Additional biological assessments of the mode of action are performed using flow cytometric techniques and fluorescence microscopy. The data obtained reveal 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.

By N‐methylation, the intramolecular lactam formation in carborane‐substituted diclofenac analogs is prevented, yielding a series of open‐chain derivatives alongside with their phenyl analogs exhibiting anticancer activity and thus offering a promising avenue for future drug development.© 2025 WILEY‐VCH GmbH