New homocamptothecins: Synthesis, antitumor activity, and molecular modeling

作者：Miao Zhenyuan; Sheng Chunquan; Zhang Wannian^*; Ji Haitao; Zhang Jing; Shao Lucheng; You Liang; Zhang Min; Yao Jianzhong; Che Xiaoyin

来源：Bioorganic & Medicinal Chemistry, 2008, 16(3): 1493-1510.

DOI：10.1016/j.bmc.2007.10.046

• homocamptothecins
• antitumor activity
• 3D-QSAR
• molecular docking

Homocamptothecins (hCPTs) represent a class of new emerging antitumor agents, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone ring (E ring) of camptothecins. Some novel 7-substituted hCPTs were designed and synthesized based on a newly developed synthetic route which couples ring A with ring C, E and D. Most of the synthesized compounds exhibit very high cytotoxic activity on tumor cell line A549. Some compounds, such as 9b, 91, and 9y, show broad in vitro antitumor spectrum and are more potent than topotecan. Three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to explain the structure-activity relationship (SAR) of the synthesized compounds. Furthermore, molecular docking was used to clarify the binding mode of the synthesized compounds to human DNA topoisomerase I. The important hydrophobic, base-pair stacking, and hydrogen-bonding interactions were observed between the hCPT derivatives and their receptor. The results from molecular modeling will guide the design of novel hCPTs with higher antitumor activity.

• 出版日期2008-2-1
• 单位中国人民解放军第二军医大学; 西北大学