Novel N-acetyl-Glycol-split heparin biotin-conjugates endowed with anti-heparanase activity.

Autor: Esposito E; Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, via G. Colombo, 81, 20133, Milan, Italy., Vlodavsky I; Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel., Barash U; Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel., Roscilli G; Takis s.r.l., Via Castel Romano 100, I-00128, Roma, Italy., Milazzo FM; R&D Alfasigma S.p.A., Via Pontina Km 30,400, Pomezia, I-00071, Roma, Italy., Giannini G; R&D Alfasigma S.p.A., Via Pontina Km 30,400, Pomezia, I-00071, Roma, Italy. Electronic address: giuseppe.giannini@alfasigma.com., Naggi A; Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, via G. Colombo, 81, 20133, Milan, Italy. Electronic address: naggi@ronzoni.it.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Jan 15; Vol. 186, pp. 111831. Date of Electronic Publication: 2019 Oct 30.
DOI: 10.1016/j.ejmech.2019.111831
Abstrakt: Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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