A potent aminonaphthalimide platinum(IV) complex with effective antitumor activities in vitro and in vivo displaying dual DNA damage effects on tumor cells

Qingpeng Wang; Yan Chen; Guoshuai Li; Yanna Zhao; Zhifang Liu; Ruiyan Zhang; Min Liu; Dacheng Li; Jun Han

doi:10.1016/j.bmcl.2019.126670

A potent aminonaphthalimide platinum(IV) complex with effective antitumor activities in vitro and in vivo displaying dual DNA damage effects on tumor cells

Bioorg Med Chem Lett. 2019 Oct 15;29(20):126670. doi: 10.1016/j.bmcl.2019.126670. Epub 2019 Sep 4.

Authors

Qingpeng Wang¹, Yan Chen², Guoshuai Li³, Yanna Zhao², Zhifang Liu², Ruiyan Zhang², Min Liu⁴, Dacheng Li⁵, Jun Han²

Affiliations

¹ Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China. Electronic address: [email protected].
² Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China.
³ Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China; State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, PR China.
⁴ Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China. Electronic address: [email protected].
⁵ Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China; Shandong Provincial Key Laboratory of Chemical Energy Storage and Novel Cell Technology, Liaocheng University, Liaocheng 252059, PR China. Electronic address: [email protected].

PMID: 31500997
DOI: 10.1016/j.bmcl.2019.126670

Abstract

A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9.

Keywords: Antitumor; DNA damage; Naphthalimide; Platinum; Prodrug.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Caspases, Initiator / genetics
Caspases, Initiator / metabolism
Cell Line, Tumor
Cisplatin / pharmacology
Coordination Complexes / chemistry*
Coordination Complexes / pharmacology
DNA / drug effects
DNA Damage
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Gene Expression Regulation / drug effects
Heterografts
Humans
Mice
Mice, Inbred BALB C
Naphthalimides / chemistry*
Neoplasms, Experimental
Organoplatinum Compounds / chemistry*
Signal Transduction

Substances

Antineoplastic Agents
Coordination Complexes
Naphthalimides
Organoplatinum Compounds
DNA
Caspases, Initiator
Cisplatin