DERIVATIVES OF DEMETHYLPENCLOMEDINE:ANTICANCER AGENTS

拟定研究的目的是合成二甲双胍（DM-PEN）的酰基、氨基甲酰基和碳酸酯衍生物，DM-PEN是二甲双胍（PEN）的抗肿瘤活性、非神经毒性代谢产物，是一种临床评价药物，其开发因临床神经毒性而终止。将分别在皮下（sc）或脑内（ic）植入的人乳腺肿瘤异种移植物（MX-1）和人CNS肿瘤异种移植物（U251）中评价这三个系列的新型药物，以提供用于选择临床候选药物的数据，用于在该快速通道申请的II期中进行拟定的进一步开发。PEN、DM-PEN及其乙酰化衍生物对离子注入的MX-1肿瘤均有抗肿瘤活性，PEN和DM-PEN对一系列人脑肿瘤移植瘤均有抗肿瘤活性（神经胶质瘤，本项目的主要目的是评估DM-PEN衍生物在脑肿瘤临床治疗中的作用，因为前者及其乙酰基衍生物已被证明对植入的MX-100具有活性。1肿瘤，PEN和DM-PEN对一系列植入SC的人神经胶质瘤和室管膜瘤具有活性。拟议的商业应用：本研究的潜在商业应用是合成一种新型DM-PEN衍生物，其可能对治疗脑肿瘤或其他类型的癌症具有临床益处。

The objective of the proposed research is to synthesize acyl, carbamyl and carbonate derivatives of demethypenclomedine (DM-PEN), the antitumor active, non-neurotoxic metabolite of penclomedine (PEN), a clinically- evaluated drug whose development was terminated because of clinical neurotoxicity. The three series of novel agents will be evaluated in a human breast tumor xenograft (MX-1) and in a human CNS tumor xenograft (U251) implanted subcutaneously (sc) or intracerebrally (ic), respectively, to provide data for selection of a clinical candidate for proposed further development in Phase II of this fast track application. PEN, DM-PEN and the acetyl derivative of DM-PEN were all active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human brain tumor xenografts (gliomas, ependymonas) implanted sc. The primary goal of this project is to evaluate derivatives of DM-PEN in the clinical treatment of brain tumors since the former and its acetyl derivative have been shown to be active against ic-implanted MX-1 tumor, and PEN and DM-PEN were active against a series of human gliomas and ependymomas implanted sc. PROPOSED COMMERCIAL APPLICATIONS: The potential commercial application of this research is the synthesis of a novel derivative of DM-PEN that may be of clinical benefit for the treatment of brain tumors or other types of cancer.