以2,8-二氧-3-乙基-6,6-亚乙二氧基-2,3,5,6,7,8-六氢-3-羟基吡喃(5,4-c)中氮茚为起始原料,经五步反应得到高喜树碱,羟甲基化后与一系列酸成酯合成了6个10-酯基高喜树碱,并利用1HNMR,MS及元素分析对其结构进行了表征.采用经典的噻唑兰(Thiazoly blue tetrazolium bromide,MTT)法测定了其体外抗肿瘤活性,活性测试结果表明3个化合物具有比阳性对照药拓扑替康增强的活性.
Thirteen homocamptothecin derivatives were synthesized and in vitro antitumor activities were evaluated by the standard MTT method. The results showed that some of the homocamptothecin derivatives had higher antitumor activity than topotecan.
Zhen Yuan MIAO Wan Nian ZHANG Jian Zhong YAO Chun Quan SHENG Yun Long SONG Hui XU Min ZHANG Jing ZHANG
The studies of novel inhibitors of DNA topoisomerase I (Topo I) have already be-come very promising in cancer chemotherapy. Identifying the new drug-binding residues is playing an important role in the design and optimization of Topo I inhibitors. The designed com-pounds may have novel scaffolds, thus will be helpful to overcome the toxicities of current camptothecin (CPT) drugs and may provide a solution to cross resistance with these drugs. Mul-tiple sequence alignments were performed on eukaryotic DNA topoisomerase I superfamily and thus the evolutionary tree was constructed. The Evolutionary Trace method was applied to iden-tify functionally important residues of human Topo I. It has been demonstrated that class-specific hydrophobic residues Ala351, Met428, Pro431 are located around the 7,9-position of CPT, indi-cating suitable substitution of hydrophobic group on CPT will increase antitumor activity. The conservative residue Lys436 in the superfamily is of particular interest and new CPT derivatives designed based on this residue may greatly increase water solubility of such drugs. It has also been demonstrated that the residues Asn352 and Arg364 were conservative in the superfamily, whose mutation will render CPT resistance. As our molecular docking studies demonstrated they did not make any direct interaction with CPT, they are important drug-binding site residues for future design of novel non-camptothecin lead compounds. This work provided a strong basis for the design and synthesis of novel highly potent CPT derivatives and virtual screening for novel lead compounds.
SONG Yunlong QI Yunpeng ZHANG Wannian SHENG Chunquan ZHANG Min YAO Jianzhong YU Jianxin MIAO Zhenyuan ZHOU Youjun ZHU Ju L(U) Jiaguo
