Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors

Benzodiazepines that consist of one alpha- and one beta-amino acid residues linked together in a seven-membered heterocyclic ring could be treated as small, rigid, cyclic dipeptides capable of exhibiting a wide range of biological activities. During our research on novel analogues of anthramycin, a tricyclic antibiotic benzodiazepine, we developed the synthesis of two benzodiazepine dimers, obtained through the cyclization of appropriate linear tripeptides. The synthesized compounds were tested on a panel of seven cancer and normal cell lines. The developed molecules exhibited promising cytotoxic activity against the lung cancer cell lines A549 and NCI-H1299 and the epidermoid carcinoma cell line A-431. Moreover, they showed significant selectivity compared to the reference cell lines (BJ-human normal skin fibroblasts and MRC-5-human normal lung cell line). When tested on two isogenic cell lines, HCT116 and HCT116p53(-/-) (colon cancer), contrary to cisplatin being used as a positive control, the obtained compounds showed a cytotoxic effect independent of the p53 protein status. For the above reasons, the obtained compounds can be considered a new group of promising anticancer agents, useful in the fight against p53-dependent drug resistance in cancers. They can also be treated as convenient, leading structures suitable for further optimization and searching for more active and selective molecules.

Automated summary

In this study, a synthesis method for two benzodiazepine dimers was developed, and the synthesized compounds showed promising cytotoxic activity against lung cancer and carcinoma cell lines while exhibiting selectivity against normal cells. These compounds can be considered as a new group of anticancer agents and convenient structures for further optimization in the search for more active and selective molecules.