Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2

Hao Qiang; Weijie Gu; DanDan Huang; Wei Shi; Qianqian Qiu; Yuxuan Dai; Wenlong Huang; Hai Qian

doi:10.1016/j.bmc.2016.03.061

Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2

Bioorg Med Chem. 2016 Aug 15;24(16):3353-8. doi: 10.1016/j.bmc.2016.03.061. Epub 2016 Apr 1.

Authors

Hao Qiang¹, Weijie Gu¹, DanDan Huang², Wei Shi¹, Qianqian Qiu¹, Yuxuan Dai¹, Wenlong Huang³, Hai Qian⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, Nanjing Sanhome Pharmaceutical Co., Ltd, Nanjing 210018, PR China.
³ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: ydhuangwenlong@126.com.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.

PMID: 27068889
DOI: 10.1016/j.bmc.2016.03.061

Abstract

The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.

Keywords: Cancers; Oxime; Synergistically collaborate; VEGFR-2; c-Met.

Publication types

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

MeSH terms

4-Aminopyridine / chemistry*
Cell Proliferation
Drug Design
Human Umbilical Vein Endothelial Cells
Humans
Inhibitory Concentration 50
Oximes / chemical synthesis
Oximes / chemistry*
Oximes / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Oximes
4-Aminopyridine
MET protein, human
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2