Total Synthesis of Plant Cycloheptapeptides as Antitumor Agents

Peptides have exhibited a wide range of bioactivities, such as anti-bacterial, antiviral and anticancer with a significant number of them being approved as clinically used drugs by the US FDA^1,2. The major therapeutic application area is oncological. The advantages of peptide agents include high activity potency and low toxicity due to their low accumulation in tissues. Cyclopeptides have been found in nature, and cycloheptapeptides are one of the common class of peptides occurred in plants.

In our search for anticancer agents from plants, we identified three cycloheptapeptides from the dry stem barks of the medicinal plant Maytenus variabilis (Loes.) C. Y. Cheng. They were demonstrated with potent anticancer activity against a panel of human cancer cell lines with IC50 values in the range of 0.05-52 nM^[3]_. A unique amino acid residue [α-amino-2, 3-dimethyl-cyclopropaneacetic acid (DMCPA)] exists in the cyclopeptides, which determined their anticancer potency. Lacking of the amino acid in the peptides led to significant loss of the activity. We aim to totally synthesize the analogues of the natural cyclopeptide analogues using commercially available amino acids in order to minimize the preparation cost for further drug development and clinical trials. We hypothesize that the replacement of the amino acid DMCPA with its structurally similar a-amino- cyclopropaneacetic acid (CPA) in the cyclopeptides would not alter the biological activity. We will further use different amino acids to replace DMCPA to obtain other analogues of the natural cyclopeptides. As a result of the synthetic study, we will be able to elucidate the structure-activity relationship and establish an efficient synthetic route to produce novel cycloheptapeptides with potent antitumor activity for future preclinical and clinical research.