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Lookup NU author(s): Professor Alan Calvert
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Our search for water-soluble quinazoline TS inhibitors that are transported into cells via the RFC, but are not substrates for FPGS, led us to the synthesis of dipeptide analogues of ICI 198583 diglutamate. Although a number of dipeptide analogues were active against isolated TS and L1210 cells in vitro, lack of in vivo stability was a problem. This was circumvented by the synthesis of modified dipeptides where either the alpha-carboxyl of the second amino acid was removed (alpha'-COOH) e.g. -L-glu-GABA or where the second amino acid was the unnatural D-enantiomer e.g.-L-glu-D-glu. Further studies were performed with the -L-glu-D-glu and its 7-CH3, 2'F modified analogue, demonstrating that they use the RFC for cell entry but are not active through polyglutamate formation. The latter compound was tested against experimental tumour models and found to have good activity.
Author(s): Jackman AL, Bisset GM, Jodrell DI, Gibson W, Kimbell R, Bavetsias V, Calvert AH, Harrap KR, Stephens TC, Smith MN
Publication type: Article
Publication status: Published
Journal: Advances in Experimental Medicine and Biology
Year: 1993
Volume: 338
Pages: 579-584
ISSN (print): 0065-2598
PubMed id: 8304184
