Antiproliferative and apoptosis-inducing activities of novel naphthalimide-cyclam conjugates through dual topoisomerase (topo) I/II inhibition

Shaoying Tan; Deheng Sun; Jiankun Lyu; Xiao Sun; Fangshu Wu; Qiang Li; Yiqi Yang; Jianxu Liu; Xin Wang; Zhuo Chen; Honglin Li; Xuhong Qian; Yufang Xu

doi:10.1016/j.bmc.2015.07.011

Antiproliferative and apoptosis-inducing activities of novel naphthalimide-cyclam conjugates through dual topoisomerase (topo) I/II inhibition

Bioorg Med Chem. 2015 Sep 1;23(17):5672-80. doi: 10.1016/j.bmc.2015.07.011. Epub 2015 Jul 15.

Authors

Shaoying Tan¹, Deheng Sun¹, Jiankun Lyu¹, Xiao Sun¹, Fangshu Wu¹, Qiang Li¹, Yiqi Yang¹, Jianxu Liu¹, Xin Wang¹, Zhuo Chen², Honglin Li³, Xuhong Qian¹, Yufang Xu⁴

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: chenzhuo@ecust.edu.cn.
³ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: hlli@ecust.edu.cn.
⁴ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yfxu@ecust.edu.cn.

PMID: 26211460
DOI: 10.1016/j.bmc.2015.07.011

Abstract

A novel series of naphthalimide-cyclam conjugates were designed and synthesized. Among them, compounds 4c, 4d, 8c and 8d which bearing long lipophilic alkyl chains, displayed comparable or more potent cytotoxic activities against human tumor cell lines than amonafide. Furthermore, the four compounds were proved to possess strong inhibition against both topoisomerase I and II. The representative compound 8c exhibited moderate DNA intercalation activity. Molecular modeling studies identified the possible interaction of compound 8c with the molecular target by forming topoisomerase/DNA/drug ternary complex. Finally, derivatives with long lipophilic alkyl chains could efficiently induce apoptosis.

Keywords: Antitumor agents; Apoptosis; DNA intercalation; Naphthalimide–cyclam conjugates; Topoisomerase I; Topoisomerase II.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Heterocyclic Compounds / metabolism*
Humans
Molecular Structure
Naphthalimides / metabolism*
Topoisomerase II Inhibitors / pharmacology*

Substances

Heterocyclic Compounds
Naphthalimides
Topoisomerase II Inhibitors
cyclam