Novel metal complexes of naphthalimide-cyclam conjugates as potential multi-target receptor tyrosine kinase (RTK) inhibitors: synthesis and biological evaluation

Shaoying Tan; Kun Han; Qiang Li; Linjiang Tong; Yiqi Yang; Zhuo Chen; Hua Xie; Jian Ding; Xuhong Qian; Yufang Xu

doi:10.1016/j.ejmech.2014.07.068

Novel metal complexes of naphthalimide-cyclam conjugates as potential multi-target receptor tyrosine kinase (RTK) inhibitors: synthesis and biological evaluation

Eur J Med Chem. 2014 Oct 6:85:207-14. doi: 10.1016/j.ejmech.2014.07.068. Epub 2014 Jul 22.

Authors

Shaoying Tan¹, Kun Han², Qiang Li¹, Linjiang Tong², Yiqi Yang¹, Zhuo Chen³, Hua Xie⁴, Jian Ding², Xuhong Qian¹, Yufang Xu⁵

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: chenzhuo@ecust.edu.cn.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yfxu@ecust.edu.cn.

PMID: 25084146
DOI: 10.1016/j.ejmech.2014.07.068

Abstract

A novel series of metal complexes of naphthalimide-cyclam conjugates were synthesized and their in vitro antitumor activities were evaluated. The newly-synthesized compounds showed huge diversity of antiproliferative potency due to variety of metal ions and length of alkyl chains, among which the Zn(II) and Cr(III) complexes exhibited comparable antiproliferative activities with amonafide via multiple tyrosine kinase inhibition. Further research revealed that the representative compound 8a displayed broad-spectrum antiproliferative activity against 15 cancer cell lines with average IC50 value 10.18 ± 3.25 μM, and effective antiangiogenic activity on human microvascular endothelial cells (HMEC-1). In brief, metal complexes of naphthalimide-cyclam conjugates were firstly designed and synthesized as multi-target tyrosine kinase inhibitors and proved of their antitumor capacities.

Keywords: Antiangiogenesis; Antiproliferation; Cyclam; Metal complexes; Naphthalimide; RTK inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Down-Regulation / drug effects
Drug Screening Assays, Antitumor
Heterocyclic Compounds / chemistry*
Humans
Naphthalimides / chemistry*
Organometallic Compounds / chemical synthesis
Organometallic Compounds / chemistry*
Organometallic Compounds / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Antineoplastic Agents
Heterocyclic Compounds
Naphthalimides
Organometallic Compounds
Protein Kinase Inhibitors
cyclam
Receptor Protein-Tyrosine Kinases