20-O-高喜树碱类化合物酯衍生物的合成与细胞毒活性.pdfVIP

中国科技论文在线 Synthesis and Cytotoxicity of Novel 20-O-linked (±)-Homocamptothecin Ester Derivatives# LI Dizao1,2, Pan Xiandao2* 5 (1. College of Pharmacy, State key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, TianJin 300071; 2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050) 10 Abstract: (±)-Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered β-hydroxylactone resulting from the insertion of a methylene (–CH2–) spacer between the alcohol moiety and the carboxyl group of the classical six-membered α-hydroxylactone ring of CPT. This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma and rather appears to improve instead of impairing its 15 activity against topoisomerase I (Topo I) compared to CPT. In an attempt to improve the antitumor activity of homocamptothecins, a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route which acylates semi-