Abstract

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2-oxoethyl]-6, 6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC50, and E-max values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity.