Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid by Aminophosphonic Acids

The synthesis of six analogues of the potent thymidylate synthase (TS) inhibitor N -[4-[ N -[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinoyl)-methyl]- N -prop-2-ynylamino]benzoyl]- L -glutamic acid 2 is described in which the glutamic acid residue has been replaced by DL -aminophosphonic acids. New anti...

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Published in:Phosphorus, sulfur, and silicon and the related elements sulfur, and silicon and the related elements, 2003-08, Vol.178 (8), p.1639-1651
Main Authors: Makowski, Maciej, Pawełczak, Krzysztof, Kafarski, Paweł, Dzik, Jolanta M., Gołos, Barbara, Balinska, Małgorzata, Rode, Wojciech
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Language:English
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Aminophosphonic Acid Analogues Of Antifolates
Antifolates
Thymidylate Synthase Inhibitors
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container_end_page 1651
container_issue 8
container_start_page 1639
container_title Phosphorus, sulfur, and silicon and the related elements
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creator Makowski, Maciej
Pawełczak, Krzysztof
Kafarski, Paweł
Dzik, Jolanta M.
Gołos, Barbara
Balinska, Małgorzata
Rode, Wojciech
description The synthesis of six analogues of the potent thymidylate synthase (TS) inhibitor N -[4-[ N -[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinoyl)-methyl]- N -prop-2-ynylamino]benzoyl]- L -glutamic acid 2 is described in which the glutamic acid residue has been replaced by DL -aminophosphonic acids. New antifolates were tested as inhibitors of TS isolated from mouse L1210 leukemic cells as well as inhibitors of growth mouse leukemic L5178Y cells. In general these modifications result in compounds that are considerably less potent than 2 as TS inhibitors with K i 's 0.17-1.10 w M. Very poor solubility in water limited their proper assay of growth cells inhibition.
doi_str_mv 10.1080/10426500307844
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subjects Aminophosphonic Acid Analogues Of Antifolates
Antifolates
Thymidylate Synthase Inhibitors
title Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid by Aminophosphonic Acids
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