Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity

BMC Cancer

Research Article

Shobith Rangappa¹  Uri Barash²  Israel Vlodavsky²  Julian E. Fuchs³  Andreas Bender³  Daniel J. Mason³  Kanchugarakoppal S. Rangappa⁴  Chakrabhavi Dhananjaya Mohan⁵  C. P. Baburajeev⁶ 

[1] Adichunchanagiri Institute for Molecular Medicine, BG Nagara, Nagamangala Taluk, district-571448, Mandya, India;Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel;Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK;Department of Studies in Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India;Department of Studies in Chemistry, University of Mysore, Manasagangotri, 570006, Mysore, India;Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, 570006, Mysore, India;Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, 560001, Bangalore, India;

关键词: Heparanase inhibitors;    triazolo-thiadiazoles;    Metastasis;    Anticancer activity;   

DOI  :  10.1186/s12885-017-3214-8

 received in 2016-02-25, accepted in 2017-03-22,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundExpression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics.MethodsIn the present work, we report the in vitro screening of a library of 150 small molecules with the scaffold bearing quinolones, oxazines, benzoxazines, isoxazoli(di)nes, pyrimidinones, quinolines, benzoxazines, and 4-thiazolidinones, thiadiazolo[3,2-a]pyrimidin-5-one, 1,2,4-triazolo-1,3,4-thiadiazoles, and azaspiranes against the enzymatic activity of human heparanase. The identified lead compounds were evaluated for their heparanase-inhibiting activity using sulfate [35S] labeled extracellular matrix (ECM) deposited by cultured endothelial cells. Further, anti-invasive efficacy of lead compound was evaluated against hepatocellular carcinoma (HepG2) and Lewis lung carcinoma (LLC) cells.ResultsAmong the 150 compounds screened, we identified 1,2,4-triazolo-1,3,4-thiadiazoles bearing compounds to possess human heparanase inhibitory activity. Further analysis revealed 2,4-Diiodo-6-(3-phenyl-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)phenol (DTP) as the most potent inhibitor of heparanase enzymatic activity among the tested compounds. The inhibitory efficacy was demonstrated by a colorimetric assay and further validated by measuring the release of radioactive heparan sulfate degradation fragments from [35S] labeled extracellular matrix. Additionally, lead compound significantly suppressed migration and invasion of LLC and HepG2 cells with IC50 value of ~5 μM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme.ConclusionsOverall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer.

【 授权许可】

CC BY   
© The Author(s). 2017