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.

Xin Wang ¹, Zhuo Chen, Linjiang Tong, Shaoying Tan, Wei Zhou, Ting Peng, Kun Han, Jian Ding, Hua Xie, Yufang Xu

Affiliations

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/KDR/Flk-1 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.

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