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

Baburajeev, C. P.

Mohan, C. D.

Shobith, R.

Mason, Daniel J.

Fuchs, Julian E.

Bender, Andreas

Barash, Uri

Vlodavsky, Israel

Basappa

Rangappa, K. S.

Springer - Publisher Connector

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

In Model Predictive Control (MPC) the control signal is computed by solving a constrained finite-time optimal control (CFTOC) problem at each sample in the control loop. The CFTOC problem can be solved by, e.g., interior-point or active-set methods, where the main computational effort in both methods is known to be the computation of the search direction, i.e., the Newton step. This is often done using generic sparsity exploiting algorithms or serial Riccati recursions, but as parallel hardware is becoming more commonly available the need for parallel algorithms for computing the Newton step is increasing. In this paper a tailored, non-iterative parallel algorithm for computing the Newton step using the Riccati recursion is presented. The algorithm exploits the special structure of the Karush-Kuhn-Tucker system for a CFTOC problem. As a result it is possible to obtain logarithmic complexity growth in the prediction horizon length, which can be used to reduce the computation time for popular state-of-the-art MPC algorithms when applied to what is today considered as challenging control problems

Nielsen, Isak

Axehill, Daniel

Publikationer från Linköpings universitet

A Parallel Structure Exploiting Factorization Algorithm with Applications to Model Predictive Control

Abstract Background 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. Methods 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. Results 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. Conclusions Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer

C. P. Baburajeev

Chakrabhavi Dhananjaya Mohan

Shobith Rangappa

Daniel J. Mason

Julian E. Fuchs

Andreas Bender

Uri Barash

Israel Vlodavsky

Kanchugarakoppal S. Rangappa

Directory of Open Access Journals

BMC Cancer

Bender, A.

University of Mysore - Digital Repository of Research, Innovation and Scholarship (ePrints@UoM)

Identification of novel class of Triazolo-Thiadiazoles as potent inhibitors of human Heparanase and their anticancer activity

Isak Nielsen

Daniel Axehill

Crossref

A parallel structure exploiting factorization algorithm with applications to Model Predictive Control

Academic Archive On-line (Linköping University, Sweden)

null Basappa

English

Background: 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. Methods: 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, thiadiazolo3,2-apyrimidin-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. Results: 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, 4triazolo3,4-b1, 3, 4thiadiazol-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 Î¼M. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme. Conclusions: Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer. Â© 2017 The Author(s)

Baburajeev, C.P.

Mohan, C.D.

Rangappa, S.

Mason, D.J.

Fuchs, J.E.

Barash, U.

Vlodavsky, I.

Basappa, .

Rangappa, K.S.

ePrints@Bangalore University

Digitala Vetenskapliga Arkivet - Academic Archive On-line

https://doaj.org/article/e01302dd50ff4695a5fd63b691790625

Identification of novel class of Triazolo-Thiadiazoles as potent inhibitors of human Heparanase and their anticancer activity

Abstract

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Springer - Publisher Connector

Publikationer från Linköpings universitet

Directory of Open Access Journals

University of Mysore - Digital Repository of Research, Innovation and Scholarship (ePrints@UoM)

Crossref

Academic Archive On-line (Linköping University, Sweden)

Crossref

ePrints@Bangalore University

Digitala Vetenskapliga Arkivet - Academic Archive On-line