| Research Abstract |
Taxanes and the vinca alkaloids are routinely used as the anti-microtubule agents in the clinic, however after long-term treatment, tumors typically become resistant to these compounds. Hence, there is a significant interest in the development of novel anti-microtubule agents for use in clinical oncology. As one of such candidates, we are focusing on a fungal product, phenylahistin (PLH), which belongs to a new class of peptidic colchicine-like microtubule-binding agents that exhibits cytotoxic activity against a wide variety of tumor cell lines. (-)-Phenylahistin (-)-1, a diketopiperazine derivative, consists of L-phenylalanine and a unique isoprenylated dehydrohistidine residue with a quaternary carbon at the 5-position of the imidazole ring. To develop more potent anti-tumor agents based on this diketopiperazine derivative, we investigated to elucidate the structural components necessary for the anti-microtubule activity of (-)-1, then performed the total synthesis of 1 for establish the synthetic route of its derivatives as well. From the biological evaluation of synthetic PLH derivatives, we found that a rigid and planar pseudo-tricyclic structure and the existence of the gem-dimethyl structure at the 5-position of the imidazole ring are important factors to elicit the potent cytotoxic activity. By utilizing this established synthetic route, we synthesized several derivatives of (-)-1, whose substituent at the 5-position of the imidazole ring was modified with different alkyl chains, to determine the effect of this moiety on the biological activity. From the evaluation of derivatives, it is suggested that the existence of the gem-dimethyl structure at this position is important to elicit higher cytotoxic activity.
Further derivatization of (-)-1 using the developed synthetic method will contribute to a better understanding on the structure-activity relationship of phenylahistin and to develop more potent antitumor agents based on the diketopiperazine structure.
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