Naphthalimides exhibit in vitro antiproliferative and antiangiogenic activities by inhibiting both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs)

Xin Wang; Zhuo Chen; Linjiang Tong; Shaoying Tan; Wei Zhou; Ting Peng; Kun Han; Jian Ding; Hua Xie; Yufang Xu

doi:10.1016/j.ejmech.2013.05.002

Naphthalimides exhibit in vitro antiproliferative and antiangiogenic activities by inhibiting both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs)

Eur J Med Chem. 2013 Jul:65:477-86. doi: 10.1016/j.ejmech.2013.05.002. Epub 2013 May 14.

Authors

Xin Wang¹, Zhuo Chen, Linjiang Tong, Shaoying Tan, Wei Zhou, Ting Peng, Kun Han, Jian Ding, Hua Xie, Yufang Xu

Affiliation

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.

PMID: 23770449
DOI: 10.1016/j.ejmech.2013.05.002

Abstract

Novel naphthalimide derivatives were designed and synthesized to modulate both topoisomerase II (topo II) and receptor tyrosine kinases (RTKs). Most target compounds exhibited effective and selective antiproliferative activities against three cancer cell lines by inhibiting topo II. The IC50 values ranged from 1.5 to 19.1 μM. Moreover, compounds 8d and 12d moderately inhibited various angiogenesis-related RTKs, including FGFR1, VEGFR2 and PDGFRα. The representative compound 8d was then proved to possess antiangiogenic activity, which was evidenced by the inhibition of migration and tube formation activities of HMEC-1 cells. To our knowledge, it is the first time naphthalimides were identified as tyrosine kinases inhibitors (TKIs) besides their conventional cytotoxicity.

Keywords: Angiogenesis; EGFR; FGFR; HMEC-1; Human Microvascular Endothelial Cells; Multitarget; Naphthalimide; PDGFR; RTK; Receptor Tyrosine Kinase; TKIs; Topo II; Topoisomerase II; Tyrosine kinase; VEGFR; epidermal growth factor receptor; fibroblast growth factor receptor; kDNA; kinetoplast DNA; platelet-derived growth factor receptor; topoisomerase II; tyrosine kinases inhibitors; vascular endothelial growth factor receptor.

Publication types

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

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Movement / drug effects
Cell Proliferation / drug effects
DNA Topoisomerases, Type II / metabolism*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HL-60 Cells
Humans
Molecular Structure
Naphthalimides / chemical synthesis
Naphthalimides / chemistry
Naphthalimides / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*
Tumor Cells, Cultured

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Naphthalimides
Protein Kinase Inhibitors
Topoisomerase II Inhibitors
Receptor Protein-Tyrosine Kinases
DNA Topoisomerases, Type II