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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Cancer 1/2017

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

BMC Cancer > Ausgabe 1/2017
C. P. Baburajeev, Chakrabhavi Dhananjaya Mohan, Shobith Rangappa, Daniel J. Mason, Julian E. Fuchs, Andreas Bender, Uri Barash, Israel Vlodavsky, Basappa, Kanchugarakoppal S. Rangappa
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12885-017-3214-8) contains supplementary material, which is available to authorized users.
C. P. Baburajeev and Chakrabhavi Dhananjaya Mohan contributed equally to this work.



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 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.


Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer.
Additional file 1: Table S1. Optimisation of mol% of SCe catalyst, and selection of medium for cyclization reaction. To optimize the reaction conditions for the synthesis of novel 1,2,4-triazolo-1,3,4-thiadiazoles, the reaction was performed in combination of 4-amino-5-phenyl-4 h-1,2,4-triazole-3-thiol and 3-oxo-3-(p-tolyl)propanoic acid as a model reaction in different concentrations of SCe and solvent. The optimal system for cyclization was 20 mol% of SCe in DMF. Table S2. Evaluation of the reuse of SCe for cyclization reaction. The recyclability of the SCe system was evaluated by employing 4-amino-5-phenyl-4 h-1,2,4-triazole-3-thiol with 3-oxo-3-(p-tolyl)propanoic acid to yield 2-(3-Phenyl-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)-1-p-tolylethanone. The catalyst was removed by filtration after each run and thoroughly washed with acetone, dried and activated at 823 K and taken for the next cycle. There was a significant reduction in the yield of the product after the second run using SCe. Figure S1. Spectral data. Scanned copy of 1H NMR, 13C NMR, and mass spectra of the indicated compounds. (DOCX 4202 kb)
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