Design, Synthesis, and Evaluation of Linear and Cyclic Peptide Analogues of Carnosine as Anticancer Agents

Abstract

Introduction: Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide, widely and abundantly distributed in the muscle and nervous tissues of animal species. Carnosine contains several beneficial biological properties, such as antiglycating and antioxidant activities. It also contains antineoplastic effects in human cell culture as well as in animal experiments; however, the clear molecular basis of this activity has not been known yet. In the present study, in order to further examine structural basis of Carnosine for the anticancer activity, some linear and cyclic Carnosine peptide analogues were synthesized and their cytotoxicity were examined. Methods and Results: Linear and cyclic Carnosine peptide analogues were synthesized with appropriate protected amino acids and reagents using solid-phase peptide synthesis strategy, and anti-neoplastic activity of the synthesized compounds was examined on cancer cell lines of HepG2 (Human Liver Cancer Cell Line) and HT-29 (Human Colorectal Adenocarcinoma Cell Line) using MTT assay and flow cytometry analysis. Safety profile of the synthesized Carnosine analogues was also examined using skin fibroblast cells. Results: Our results showed that Carnosine analogues were toxic against HepG2 and HT-29 cell lines with a mean IC50 value of 12.7 μg/mL. Flow cytometry analysis showed that such toxic activity could be, at least partly, through apoptosis induction. Conclusions: According to our experiments, in overall, compound 3b can be a good candidate for the further development of safe anticancer agents. On the other hand, the considerable toxicity of cyclic peptide analogues of Carnosine, 1c and 2c, on the cancerous cell lines along with their high safety profiles on the normal skin cells, make them attractive for further works on finding anticancer agents with peptide structure, giving better physicochemical properties for oral administration.