Development of Anticancer and Antiviral Agents Based on Diketopiperazine as a Bio-function-Mimicking Molecular Platform

为了了解二酮基哌嗪(DKP)模板作为生物功能模拟分子平台在药物化学中的应用，本研究计划建立一种简便的DKP的合成方法，并开发一种基于DKP结构的新型抗癌药物。结果表明：1)一种在DKP环的α，β位具有脱氢结构的单脱氢DKP衍生物的简便合成新方法。2)将该方法成功地应用于天然抗癌剂苯基拉西汀的手性衍生物的合成。3)对DKP进行了结构优化，得到了一种高效的抗癌衍生物，并开发出了一种既有效又稳定的抗细胞色素P450代谢的衍生物。4)此外，在抗癌药物方面，还开发了一种高度难溶的抗微管剂的水溶性前药；5)以合成二酮基哌嗪所需的手性氨基酸为原料，开发了一种新型高效的固载手性辅助剂。

To understand the usefulness of diketopiperazine (DKP) template as a bio-function-mimicking molecular platform in medicinal chemistry, in this research project, we planed to establish a convenient synthetic method for DKP and develop a new anticancer agent based on the DKP structure. As results, 1) a new convenient synthetic procedure for monodehydro-DKP derivatives which has a dehydro-structure at anα,β-position of the DKP ring. 2) this method was successfully applied to the synthesis of a chiral derivative of naturally occurring anticancer agent, phenylahistin. 3) a structural optimization of DKP was carried out to obtain a highly potent anticancer derivative, and a derivative which is not only potent but also stable against cytochrome P450 metabolism was developed. 4) Additionally, in an anticancer drug, a water-soluble prodrug for highly insoluble anti-microtubule agent was also developed, and 5) New efficient solid-supported chiral auxiliary for the preparation of chiral amino acids, which are needed for diketopiperazine synthesis as starting materials, was developed.