title: Gamma-linked dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8- dideazafolate as antitumour agents.
abstract: 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.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
authors.forename: G M
authors.initials: GM
authors.lastname: Bisset
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: W
authors.initials: W
authors.lastname: Gibson
authors.forename: R
authors.initials: R
authors.lastname: Kimbell
authors.forename: V
authors.initials: V
authors.lastname: Bavetsias
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
authors.forename: K R
authors.initials: KR
authors.lastname: Harrap
authors.forename: T C
authors.initials: TC
authors.lastname: Stephens
authors.forename: M N
authors.initials: MN
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D004151:Dipeptides; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000627:therapeutic use* / Q000633:toxicity; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D011799:Quinazolines / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013876:Thiophenes; D005492:Folic Acid; D013940:Thymidylate Synthase; C068874:raltitrexed; C059966:ICI 198583