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

• Published in: Phosphorus, sulfur, and silicon and the related elements Vol. 178; no. 8; pp. 1639 - 1651
• Main Authors: Makowski, Maciej, Pawełczak, Krzysztof, Kafarski, Paweł, Dzik, Jolanta M., Gołos, Barbara, Balinska, Małgorzata, Rode, Wojciech
• Format: Journal Article
• Language: English
• Published: Taylor & Francis Group 01-08-2003
• Subjects: Aminophosphonic Acid Analogues Of Antifolates; Antifolates; Thymidylate Synthase Inhibitors
• ISSN: 1042-6507; 1563-5325
• DOI: 10.1080/10426500307844

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N -prop-2-ynylamino]benzoyl]- L -glutamic acid 2 is described in which the glutamic acid residue has been replaced by DL -aminophosphonic acids.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.