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Sci Rep. 2016 Sep 16;6:33434. doi: 10.1038/srep33434.

Discovery and Optimization of N-Substituted 2-(4-pyridinyl)thiazole carboxamides against Tumor Growth through Regulating Angiogenesis Signaling Pathways.

Author information

1
Joint Research Center for Translational Medicine of East China Normal University and Fengxian District Central Hospital, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
2
Joint Research Center for Translational Medicine of East China Normal University and Fengxian District Central Hospital, Fengxian Hospital affiliated to Southern Medical University, Shanghai, 201499, China.
3
Department of Computer Science and Technology, East China Normal University, Shanghai 200241, China.

Abstract

Inhibition of angiogenesis is considered as one of the desirable pathways for the treatment of tumor growth and metastasis. Herein we demonstrated that a series of pyridinyl-thiazolyl carboxamide derivatives were designed, synthesized and examined against angiogenesis through a colony formation and migration assays of human umbilical vein endothelial cells (HUVECs) in vitro. A structure-activity relationship (SAR) study was carried out and optimization toward this series of compounds resulted in the discovery of N-(3-methoxyphenyl)-4-methyl-2-(2-propyl-4-pyridinyl)thiazole-5-carboxamide (3k). The results indicated that compound 3k showed similar or better effects compared to Vandetanib in suppressing HUVECs colony formation and migration as well as VEGF-induced angiogenesis in the aortic ring spreading model and chick embryo chorioallantoic membrane (CAM) model. More importantly, compound 3k also strongly blocked tumor growth with the dosage of 30 mg/kg/day, and subsequent mechanism exploration suggested that this series of compounds took effect mainly through angiogenesis signaling pathways. Together, these results suggested compound 3k may serve as a lead for a novel class of angiogenesis inhibitors for cancer treatments.

PMID:
27633259
PMCID:
PMC5025770
DOI:
10.1038/srep33434
[Indexed for MEDLINE]
Free PMC Article

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