DERIVATIVES OF DEMETHYLPENCLOMEDINE:ANTICANCER AGENTS

本研究的目的是合成脱甲基苯科美定（DM-PEN）的酰基、氨甲酰和碳酸盐衍生物，脱甲基苯科美定是彭洛美定（PEN）的抗肿瘤、无神经毒性代谢物，彭洛美定是一种临床评价药物，但由于临床神经毒性而终止了其开发。这三个系列的新药将分别在人乳腺肿瘤异种移植物（MX-1）和人中枢神经系统肿瘤异种移植物（U251）皮下植入（sc）或脑内植入（ic）中进行评估，为选择临床候选药物提供数据，以便在该快速通道申请的II期进一步开发。PEN、DM-PEN及DM-PEN的乙酰基衍生物对ic植入的MX-1肿瘤均有活性，并且PEN和DM-PEN对一系列移植的人类脑肿瘤（胶质瘤、室管膜单胞菌）均有活性。本项目的主要目的是评价DM-PEN衍生物对ic植入的MX-1肿瘤的临床治疗作用，因为PEN及其乙酰基衍生物已被证明对ic植入的MX-1肿瘤有活性。以及PEN和DM-PEN对一系列植入sc的人类胶质瘤和室管膜瘤有活性。拟议的商业应用：本研究的潜在商业应用是合成一种新的DM-PEN衍生物，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.