DEVELOPMENT AND EVALUATION OF SELECTIVE MELANOTROPINS OF CYCLIZED STRUCTURES, AND SMALL MOLECULE DERIVATIVES OF PIPERINE FOR MELANOMA CELL DEATH

Abstract

This study of the melanocortin system is focused on the development of three series of potential melanotropins and evaluating their interaction and stimulation of the melanocortin system. The melanocortin system is involved in many important physiological processes. The MC1R receptor functions in skin pigmentation and is involved in melanoma, MC3R and MC4R are involved in the regulation of energy metabolism, as well as feeding behaviors including anorexia and obesity, MC4R is also involved in sexual dysfunction, and MC5R is involved in exocrine gland function. The compounds in this study are designed for stability in vivo in order to be available as an oral drug for diseases related to the physiological functions related to the melanocortin system. The ACE series utilizes a small molecule structure to increase stability and the AC series of somatostatin-like peptides, a related GPCR, was designed as a cyclized peptide with a cysteine knot motif to increase drug stability. The ACE series was found to be selective for binding and stimulation of MC5R. The compounds AC2 and AC5, and AC7 at high concentrations, show preference but are nonselective as MC5R antagonists or potentially as MC1R agonists, and AC6 shows large binding affinity but is nonselective between MC1R, MC3R, and MC5R. The piperine derivatives series were derived from piperine, known to be cytotoxic to melanoma cells, and were designed for increased specificity and cytoxicity for melanoma cells, and the derivatives Pip-H4, Pip-Meso, and Pip-Triazole had the highest effect of cell death on melanoma cells.