Quinazoline Antifolate Thymidylate Synthase Inhibitors:  γ-Linked l-d, d-d, and d-l Dipeptide Analogues of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic Acid (ICI 198583)

• Published in: Journal of medicinal chemistry Vol. 39; no. 1; pp. 73 - 85
• Main Authors: BAVETSIAS, Vassilios, JACKMAN, Ann L., KIMBELL, Rosemary, GIBSON, William, BOYLE, F. Thomas, BISSET, Graham M. F.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05.01.1996
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Chemistry; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Exact sciences and technology; Folic Acid - analogs & derivatives; Folic Acid - pharmacology; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Folic Acid Antagonists - pharmacology; General aspects; Leukemia L1210 - drug therapy; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Mice; Molecular Structure; Organic chemistry; Peptides; Pharmacology. Drug treatments; Preparations and properties; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Thymidylate Synthase - antagonists & inhibitors; Tumor Cells, Cultured; Antineoplastic agent; Enzyme; Nitrogen heterocycle; Transferases; Quinazoline derivatives; Enzyme inhibitor; Cytotoxicity; L1210-Leukemia; Liquid phase; Thymidylate synthase; In vitro; Antifolate; Methyltransferases; Antimetabolic; Structure activity relation; Enantiomer; Bicyclic compound; Dipeptides; Peptide synthesis; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950471+

The syntheses of gamma-linked L-D, D-D, and D-L dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) are described. The general methodology for the synthesis of these molecules involved the preparation of the dipeptide derivatives employing solution phase peptide synthesis followed by condensation of the dipeptide free bases with the appropriate pteroic acid analogue via diethyl cyanophosphoridate (DEPC) activation. In the final step, tert-butyl esters were removed by trifluoroacetic acid (TFA) hydrolysis. Z-L-Glu-OBut-gamma-D-Ala-OBut, for example, was prepared from alpha-tert-butyl N-(benzyloxycarbonyl)-L-glutamate and tert-butyl D-alaninate via isobutyl-mixed anhydride coupling. The Z-group was removed by catalytic hydrogenolysis and the resulting dipeptide free base condensed with 2-desamino-2-methyl-N10-propargyl-5,8-dideazapteroic acid via DEPC coupling. Finally, tert-butyl esters were removed by TFA hydrolysis to give ICI 198583-gamma-D-Ala. The compounds were tested as inhibitors of thymidylate synthase and L1210 cell growth. Good enzyme and growth inhibitory activity were found with gamma-linked L-D dipeptides, the best examples being the Glu-gamma-D-Glu derivative 35 (Ki = 0.19 nM, L1210 IC50 = 0.20 +/- 0.017 microM) and the Glu-gamma-D-alpha-aminoadipate derivative 39 (Ki = 0.12 nM, L1210 IC50 = 0.13 +/- 0.063 microM). In addition, ICI 198583 L-gamma-D-linked dipeptides were resistant to enzymatic degradation in mice.