Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity

被引：19

作者：

Messore, Antonella ^{[1
]}

Madia, Valentina Noemi ^{[1
]}

Pescatori, Luca ^{[1
]}

Saccoliti, Francesco ^{[1
]}

Tudino, Valeria ^{[1
]}

De Leo, Alessandro ^{[1
]}

Bortolami, Martina ^{[1
]}

De Vita, Daniela ^{[1
]}

Scipione, Luigi ^{[1
]}

Pepi, Federico ^{[1
]}

Costi, Roberta ^{[1
]}

Rivara, Silvia ^{[2
]}

Scalvini, Laura ^{[2
]}

Mor, Marco ^{[2
]}

Ferrara, Fabiana Fosca ^{[3
]}

Pavoni, Emiliano ^{[3
]}

Roscilli, Giuseppe ^{[3
,4
]}

Cassinelli, Giuliana

Milazzo, Ferdinando M. ^{[5
]}

Battistuzzi, Gianfranco ^{[5
]}

Di Santo, Roberto ^{[1
]}

Giannini, Giuseppe ^{[5
]}

机构：

[1] Sapienza Univ Roma, Inst Pasteur, Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farm, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[2] Univ Parma, Dipartimento Sci Alimenti & Farm, Parco Area Sci 27-A, I-43124 Parma, Italy

[3] Takis SRL, Via Castel Romano 100, I-00128 Rome, Italy

[4] Fdn IRCCS Ist Nazl Tumori, Unita Farmacol Mol, Dipartimento Ric Appl & Sviluppo Tecnol, I-20133 Milan, Italy

[5] R&D Alfasigma SpA, Via Pontina Km 30400, I-00071 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 23期

关键词：

ANTITUMOR EFFICACY; ACCURATE DOCKING; ACID DERIVATIVES; TUMOR-GROWTH; SULFATE; IDENTIFICATION; INHIBITOR; MECHANISMS; EXPRESSION; DISCOVERY;

D O I：

10.1021/acs.jmedchem.8b01497

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Heparanase is the only mammalian endo-beta-D-glucuronidase involved in a variety of major diseases. The up-regulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti-cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells.

引用

页码：10834 / 10859

页数：26

共 60 条

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