Synthesis and cytotoxic evaluation of novel Nα-1, 4-benzenedicarbonyl bridged cyclo-pentapeptide candidates.

Cancer is the second most common cause of death worldwide, with mortality about to surpass that from cardiovascular diseases. Therapeutic peptides present several advantages over conventional cancer treatments such as ease of synthesis, higher target selectivity and lower toxicity. As a continuation of our previous recent reports on anticancer cyclic peptides, novel Nα-1, 4-benzenedicarbonyl bridged cyclo-pentapeptides were newly synthesized and evaluated for cytotoxic activity using MTT growth inhibition assay. Interestingly, compound 9, namely Cyclo-[Nα-1, 4-benzenedicarbonyl-bis-(Gly-L-Phe)-L–Lys]-OMe showed higher inhibitory activity on breast (MCF-7) and liver (HepG-2) cell lines, with IC50 values 4.04 and 2.82 µg/ml respectively, compared to the reference drugs Tamoxifen (8.31 and 10.9 µg/ml) and Doxorubicin (2.97 and 3.73 µg/ml). Cytotoxic activity of compound 9 was further investigated on five other cell lines, namely colon (CaCo-2), prostate (PC-3), cervical (HeLa), larynx (Hep-2) and breast (T47D) cancer cells. Compound 9 was found to be more potent than doxorubicin in three cell lines, (T47D, HeLa and PC-3), and almost as potent in CaCo-2 cell line, consequently representing a very promising anticancer candidate. Assessment of its possible mechanism of action as multi-targeted kinase inhibitor will be investigated.