title: The synthesis and thymidylate synthase inhibitory activity of L-gamma-L-linked dipeptide and L-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).
abstract: Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.
authors.affiliation: CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Cancer Research Campaign Laboratories, Sutton, Surrey, England.
authors.forename: G M
authors.initials: GM
authors.lastname: Bisset
authors.forename: V
authors.initials: V
authors.lastname: Bavetsias
authors.forename: T J
authors.initials: TJ
authors.lastname: Thornton
authors.forename: K
authors.initials: K
authors.lastname: Pawelczak
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
authors.forename: L R
authors.initials: LR
authors.lastname: Hughes
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D004151:Dipeptides; C089709:N-(N-(4-(N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-2-propynylamino)benzoyl)-gamma-glutamyl)-2-aminoadipic acid; D015074:2-Aminoadipic Acid; D018698:Glutamic Acid; D005492:Folic Acid; D013940:Thymidylate Synthase; D006867:Hydrolases; C059966:ICI 198583