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Quinoxaline chemistry: Part 15: 4-[2-Quinoxalylmethylenimino]-benzoylglutamates and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as analogues of classical antifolate agents: Synthesis, elucidation of structures and in vitro evaluation of antifolate and anticancer activities

Loriga, Mario and Piras, Sandra and Paglietti, Giuseppe and Costi, Maria Paola and Venturelli, Alberto (2003) Quinoxaline chemistry: Part 15: 4-[2-Quinoxalylmethylenimino]-benzoylglutamates and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as analogues of classical antifolate agents: Synthesis, elucidation of structures and in vitro evaluation of antifolate and anticancer activities. Il Farmaco, Vol. 58 (1), p. 51-61. ISSN 0014-827X. Article.

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DOI: 10.1016/S0014-827X(02)00005-8

Abstract

We report on an extension of our previous discovery of in vitro anticancer activity of trifluoromethylquinoxalines as analogues of classical and non-classical antifolic methotrexate and trimetrexate. In this case a small number of Schiff bases were obtained from the reaction of 2-bromethyl-3-R-6(7)trifluoromethylquinoxaline and ethyl p-aminobenzoylglutamate, ethyl p-aminobenzoate, p-toluidine instead of the expected 4-[2-quinoxalyl]methyl-N-methylanilino derivatives, which in turn formed with N-methylanilino derivatives. The reaction mechanism has been put forward. Structure elucidation of both Schiff bases and N-methylanilino analogues was achieved by a combination of 1H and 13C NMR spectra and hetcor experiments. Compounds 3a, 3b, 3c, 8, 11,12, 13, Ie were tested in antifolic enzyme assay [Lactobacillus casei (LcTS), Leishmania major (LmTs), human Thymidylate synthase (hTs), human TS, human dihydrofolate reductase (hDHFR)] while compounds 3a, 3b, 3c were tested for anticancer activity. These results seem to indicate that the Schiff bases are somewhat active either as anticancer or as folate inhibitors, while compound Ie was selectively active against hDHFR with an inhibition constant (Ki) of 200 nM with a specificity of about 1000-folds with respect to hTS.

Item Type:Article
ID Code:1398
Status:Published
Refereed:Yes
Uncontrolled Keywords:Antifolate agents, anticancer agents, enzyme inhibition, dihydrofolate reductase and tymidylate synthase inhibitors, 1H and 13C NMR trifluoromethylquinoxalines
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:Elsevier
ISSN:0014-827X
Copyright Holders:© 2003 Éditions scientifiques et médicales Elsevier
Additional Information:Pubblicato online il 13 dicembre 2002.
Deposited On:18 Aug 2009 10:05

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