Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC500.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.

Novel benzazole derivatives endowed with potent antiheparanase activity / Madia, VALENTINA NOEMI; Messore, Antonella; Pescatori, Luca; Saccoliti, Francesco; Tudino, Valeria; DE LEO, Alessandro; Bortolami, Martina; Scipione, Luigi; Costi, Roberta; Rivara, Silvia; Scalvini, Laura; Mor, Marco; Fosca Ferrara, Fabiana; Pavoni, Emiliano; Roscilli, Giuseppe; Cassinelli, Giuliana; M Milazzo, Ferdinando; Battistuzzi, Gianfranco; DI SANTO, Roberto; Giannin, Giuseppe. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:15(2018), pp. 6918-6936. [10.1021/acs.jmedchem.8b00908]

Novel benzazole derivatives endowed with potent antiheparanase activity

Valentina Noemi Madia;Antonella Messore;Luca Pescatori;Francesco Saccoliti;Valeria Tudino;Alessandro De Leo;Martina Bortolami;Luigi Scipione;Roberta Costi;Roberto Di Santo
;
2018

Abstract

Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC500.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.
File allegati a questo prodotto
File Dimensione Formato  
Madia_Novel-benzazole-derivatives_2018.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 4.54 MB
Formato Adobe PDF
4.54 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1176836
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 24
social impact