Enhancing the chemosensitivity of HepG2 cells towards cisplatin by organoselenium pseudopeptides

Organoselenium compound 23 was able to chemo-sensitize HepG2 cells towards cisplatin up-to 27-fold. Cell cycle studies indicate that organoselenium 23 arrested cells at the S phase, and induced apoptosis via ROS modulation. Organoselenium compound 23 can therefore act as lead structures both for the development of novel chemotherapeutics and chemo-sensitizers for effective treatment of HCC. [Display omitted] •Organoselenium pseudopeptides and tetrazoles were synthesized.•Compounds were evaluated for their cytotoxicity against HepG2.•Compounds chemosensitized HepG2 towards cisplatin.•Diselenide 23 arrested cells at the S phase.•Diselenide 23 induced apoptosis via ROS modulation. Despite all recent advances in the treatment of hepatocellular carcinoma (HCC), chemotherapy resistance still represents a major challenge in its successful clinical management. Chemo-sensitization offers an attractive strategy to counter drug resistance. Herein we report the identification of novel organoselenium-based pseudopeptides as promising highly effective chemo-sensitizers in treating HCC with cisplatin. A series of functionalized pseudopeptide- (5–9 and 17–19), peptidomimetic- (10–12 and 20–23), and tetrazole-based (13–16 and 24–27) organoselenium compounds were synthesized via isonitrile-based multicomponent reactions from two novel selenium-containing isocyanides. All compounds were evaluated for their cytotoxicity against HepG2 and the non-cytotoxic doses were used to restor the sensitivity of the cells to cisplatin. New organoselenium compounds (7, 9, 15, or 23) led to an effective chemo-sensitization of HepG2 cells towards cisplatin (up-to 27-fold). Cell cycle studies indicate that the most potent peptidomimetic diselenide 23 arrested cells at the S phase and induced apoptosis via ROS modulation.