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

• Published in: Biomolecules (Basel, Switzerland) Vol. 13; no. 2; p. 291
• Main Authors: Speina, Elżbieta, Wilczek, Marcin, Mieczkowski, Adam
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.02.2023; MDPI
• Subjects: Amino acids; Anthramycin; Antineoplastic Agents - pharmacology; Antitumor agents; Benzodiazepines; Cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell Proliferation; Chromatography; Cisplatin; Colon cancer; Cyclic dipeptides; Cytotoxicity; Drug Resistance; Fibroblasts; Humans; Lung cancer; Lung Neoplasms; p53 Protein; Peptides - pharmacology; Potash; Potassium; Prevention; selectivity; Testing; Tumor cell lines; Tumor Suppressor Protein p53; Tumors; Poland; United States > US; Germany; selectivity; benzodiazepines; drug resistance; cytotoxicity; p53 protein
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom13020291

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.