title: Discovery and Optimization of N-Substituted 2-(4-pyridinyl)thiazole carboxamides against Tumor Growth through Regulating Angiogenesis Signaling Pathways.
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.
authors.affiliation: 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.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Wenshu
authors.initials: W
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Zhenliang
authors.initials: Z
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Pei
authors.affiliation: 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.
authors.forename: Yangrui
authors.initials: Y
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Shao
authors.affiliation: Department of Computer Science and Technology, East China Normal University, Shanghai 200241, China.
authors.forename: Zhenran
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.affiliation: 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.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D003114:Colony-Forming Units Assay; D015195:Drug Design; D055808:Drug Discovery; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D010880:Piperidines; D011799:Quinazolines; D013844:Thiazoles; C452423:vandetanib