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Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors

Carosati, Emanuele and Sforna, Gianluca and Pippi, Massimiliano and Marverti, Gaetano and Ligabue, Alessio and Guerrieri, Davide and Piras, Sandra and Guaitoli, Giambattista and Luciani, Rosaria and Costi, Maria Paola and Cruciani, Gabriele (2010) Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors. Bioorganic & Medicinal Chemistry, Vol. 18 (22), p. 7773-7785. eISSN 1464-3391. Article.

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DOI: 10.1016/j.bmc.2010.09.065

Abstract

In the process of drug discovery the lead-identification phase may be critical due to the likely poor safety profile of the candidates, causing the delay or even the abandonment of a certain project. Nowadays, combining molecular modeling and in vivo cellular evaluation can help to identify compounds with an enhanced safety profile. Previously, two quinoxalines have been identified as inhibitors of the folate-dependent proteins belonging to the thymidylate synthase cycle. Unfortunately, cytotoxic activity against a panel of cisplatin(cDDP)-sensitive ovarian carcinoma cell lines and their resistant counterparts was coupled with toxicity to non-tumorigenic Vero cells. Here we describe the application of a ligand-based virtual screening, and several [1,2,4]triazolo[4,3-a]quinoxalines were optimized to improve their ADME-tox profile. The resulting 4-(trifluoromethyl)-1-p-tolyl-[1,2,4]triazolo[4,3-a]quinoxaline (24), which interferes intracellularly with DHFR and TS reducing the protein levels like 5-FU, but without inducing TS ternary complex formation, was 2-times less toxic in vitro than cisplatin and 5-FU.

Item Type:Article
ID Code:5503
Status:Published
Refereed:Yes
Uncontrolled Keywords:Folate cycle inhibitors, Triazolo-quinoxalines, ligand-based virtual screening, FLAP, ovarian carcinoma cell lines
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:Pergamon-Elsevier Science
eISSN:1464-3391
Deposited On:04 Mar 2011 16:49

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