title: Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity.
abstract: Expression 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.
  
  
  
  In 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.
  
  
  
  Among 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 IC50value of ~5 μM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme.
  
  
  
  Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer.
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore, 560001, India.
authors.forename: C P
authors.initials: CP
authors.lastname: Baburajeev
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, India.|Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, 570006, India.
authors.forename: Chakrabhavi Dhananjaya
authors.initials: CD
authors.lastname: Mohan
authors.affiliation: Adichunchanagiri Institute for Molecular Medicine, BG Nagara, Nagamangala Taluk, Mandya, district-571448, India.
authors.forename: Shobith
authors.initials: S
authors.lastname: Rangappa
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mason
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Barash
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. vlodavsk@mail.huji.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore, 560001, India. salundibasappa@gmail.com.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, India. rangappaks@yahoo.com.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D013830:Thiadiazoles / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D000099175:Heparanase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D013830:Thiadiazoles; D014230:Triazoles; D000099175:Heparanase
keywords: Anticancer activity; Heparanase inhibitors; Metastasis; triazolo-thiadiazoles