Synthesis and Pharmacological Evaluation of Novel Homocamptothecin-Dihydropyridine Derivative Conjugates as Potent Topoisomerase I Inhibitors
Ling-Jian Zhu A , Chun-Lin Zhuang A , Ning Lei B , Chun-Quan Sheng A C , Wei Guo A , Zhen-Yuan Miao A C , Wen-Feng Liu A , Jian-Zhong Yao A and Wan-Nian Zhang A CA School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
B Department of Quality Assurance, Lian Yun Gang JARI Pharmaceutical Co., Ltd, 18 Zhenhua Road, Lianyungang 222100, China.
C Corresponding authors. Email: zhangwnk@hotmail.com; miaozhenyuan@hotmail.com; shengcq@hotmail.com
Australian Journal of Chemistry 64(10) 1390-1396 https://doi.org/10.1071/CH11091
Submitted: 25 February 2011 Accepted: 3 June 2011 Published: 23 August 2011
Abstract
Homocamptothecins (hCPT) represent a new generation of antitumour agents targeting DNA topoisomerase I. The expanded seven-membered lactone E-ring that characterizes hCPT enhances the plasma stability of the drug and reinforces the inhibition of topoisomerase I (Topo I) compared with conventional six-membered CPT. In an attempt to improve the antitumour activity of hCP, a series of novel hCPT derivatives conjugating with dihydropyridine derivates were designed and synthesized based on a synthetic route that couples 7-formylhomocamptothecin with different dihydropyridine derivates. Most of the synthesized compounds exhibited good cytotoxic activity on tumour cell line A549, MDA-MB-435, and HCT116. Furthermore, this class of compounds showed superior Topo I inhibition activity comparable to or higher than CPT.
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