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

Biomolecules. 2023 Feb 3;13(2):291. doi: 10.3390/biom13020291.

Abstract

Benzodiazepines that consist of one α- and one β-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.

Keywords: benzodiazepines; cytotoxicity; drug resistance; p53 protein; selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Benzodiazepines
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance
  • Humans
  • Lung Neoplasms*
  • Peptides / pharmacology
  • Tumor Suppressor Protein p53

Substances

  • Tumor Suppressor Protein p53
  • Benzodiazepines
  • Antineoplastic Agents
  • Peptides

Grants and funding

This research received no external funding.