Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity

Madia, Valentina Noemi; Messore, Antonella; Pescatori, Luca; Saccoliti, Francesco; Tudino, Valeria; Leo, Alessandro De; Bortolami, Martina; Scipione, Luigi; Costi, Roberta; Rivara, Silvia; Scalvini, Laura; Mor, Marco; Ferrara, F; Pavoni, Emiliano; Roscilli, Giuseppe; Cassinelli, Giuliana; Milazzo, Ferdinando Maria; Battistuzzi, Gianfranco; Santo, Roberto Di; Giannini, Giuseppe

doi:10.1021/acs.jmedchem.8b00908

Cited by 35 publications

(71 citation statements)

References 47 publications

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“…Four newly synthesized compounds were already tested for their ability to inhibit Heparanase activity by using an in vitro assay [19,21]. The compound RDS3337 (Figure 1) revealed the highest anti-Heparanase activity among the tested compounds, showing nanomolar potency.…”

Section: Preliminary Analysis Of Activity and Cytotoxic Effect Of Hepmentioning

confidence: 99%

“…Due to their properties to be properly designed to have favorable pharmacokinetic and oral availability, small molecules are particularly desirable. Some benzoxazole derivates, in the group of synthetic small molecules, have been described as Heparanase inhibitors; among these benzoxazol-5-yl acetic acid showed promising properties as Heparanase inhibitors [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Capozzi

Riitano

Recalchi

et al. 2020

Preprint

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Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity associated with the presence of “anti-phospholipid antibodies”. Thrombosis may be the result of a hypercoagulable state related to activation of endothelial cells and platelets by anti-2-glycoprotein I (β2-GPI) antibodies. Anti-β2-GPI antibodies induce a proinflammatory and procoagulant phenotype in these cells that, after activation, express Tissue Factor (TF), the major initiator of the clotting cascade, playing a role in thrombotic manifestations. Moreover, TF expression may also be induced by Heparanase, an endo--D-glucuronidase, that generates heparan sulfate fragments, regulating inflammatory responses. In this study we analyzed, in human platelets and endothelial cells, the effect of a new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivative (RDS3337), able to inhibit Heparanase activity, on signal transduction pathway leading to TF expression triggered by anti-β2-GPI. Platelets and endothelial cells were incubated with affinity purified anti-β2-GPI after pretreatment with RDS3337. Cell lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK1), phospho-p65 nuclear factor kappa B (NF-κB) and TF by Western blot. IRAK phosphorylation and consequent NF-κB activation, as well as TF expression, triggered by anti-β2-GPI treatment were significantly prevented by previous pretreatment with RDS3337. In the same vein, pretreatment with RDS3337 prevented platelet aggregation and ATP release triggered by anti-β2-GPI antibodies. These findings support the view of Heparanase involvement in a prothrombotic state related to APS syndrome, suggesting a novel target to regulate overexpression of procoagulant protein(s).

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Section: Preliminary Analysis Of Activity and Cytotoxic Effect Of Hepmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Capozzi

Riitano

Recalchi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…The changes in the five-membered ring are not so easily rationalised. (16) 104.46(4)104.46(11) a(C4-C5-N1)106.42 (16) 106.23(4)106.29(12) a(C5-N1-N2)113.07 (30) 113.24 (5) 113.22 (15) [a] Using the data from ref. [51] augmented by MP2/cc-pVTZa nharmonic force field calculations.…”

Section: Compoundmentioning

confidence: 99%

“…[24][25][26][27] Moreover,s everala zole derivatives (for example, fluconazole) have antifungal properties. [28] Benzazoles are under study as agentsa gainst tuberculosis [29] and some derivatives show antiheparanase activity, [30] which may potentially lead to anticancer treatments. In this work, we focus on indazole [31][32][33][34] and the subtle effect of aromatic bond length alternation.…”

Section: Introductionmentioning

confidence: 99%

Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

Uriarte

Reviriego

Calabrese

et al. 2019

Chemistry A European J

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Bond length alternation is a chemical phenomenon in benzene rings fused to other rings, which has been mainly predicted theoretically. Its physical origin is still not clear and has generated discussion. Here, by using a strategy that combines microwave spectroscopy, custom‐made synthesis and high‐level ab initio calculations, we demonstrate that this phenomenon is clearly observed in the prototype indazole molecule isolated in the gas phase. The 1H‐indazole conformer was detected by rotational spectroscopy, and its 17 isotopologues resulting from single and double heavy atom substitution (13C and 15N) were also unambiguously observed. Several experimental structures were determined and, in particular, the most useful semi‐experimental equilibrium structure (reSE), allowed determination of the heavy atom bond lengths to milli‐Ångstrom precision. The experimentally determined bond length alternation is estimated to correspond to 60:40 contributions from the two resonant forms of 1H‐indazole.

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“…Heparanase has been considered a drug target for cancer and inflammation [39][40][41][42][43][44] . Nonetheless, only four saccharide-based inhibitors have been assessed in clinical trials 1,45 .…”

Section: Hadp-assisted High-throughput Inhibitor Screeningmentioning

confidence: 99%

Ultrasensitive small molecule fluorogenic probe for human heparanase

Schleyer

Bryan

et al. 2020

Preprint

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Heparanase is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, assays developed for this enzyme so far have suffered prohibitive drawbacks. Here we present an ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.Heparanase, an endo-β-glucuronidase of the glycoside hydrolase 79 (GH79) family 1,2 , is responsible for the cleavage of heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPG) 3 . These protein-polysaccharide conjugated macromolecules, abundantly expressed in the extracellular matrix (ECM), play an essential structural role in maintaining the ECM integrity.Moreover, the HS side chains bind to an array of biological effector molecules, such as growth factors, chemokines, and cytokines, thereby serving as their reservoir that can liberate the desired signaling molecules when needed.

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Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity

Cited by 35 publications

References 47 publications

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Bond Length Alternation Observed Experimentally: The Case of 1H‐Indazole

Ultrasensitive small molecule fluorogenic probe for human heparanase

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