Quinazoline Antifolates Inhibiting Thymidylate Synthase: Synthesis of γ-Linked Peptide and Amide Analogues of 2-Desamino-2-Methyl-N10-Propargyl-5,8-Dideazafolic Acid (ICI 198583)10-Propargyl-5,8-Dideazafolic Acid (ICI 198583)

Abstract

Thymidylate Synthase (TS) inhibitors such as ICI D16941 and to lesser extent ICI 1985832 rely on their poly-γ-glutamate metabolites for their antitumour activity. The polyglutamate metabolites are more potent inhibitors of TS than the parent monoglutamate forms and in addition, their polyionic nature leads to prolonged retention within the cells. However, drugs dependent on polyglutamation may have some disadvantages such as a) lack of activity in tumours expressing low levels of, or an altered expression of, folylpolyglutamate synthetase (FPGS) or b) prolonged normal tissue toxicities caused by polyglutamate retention. For these reasons, we were interested in designing and synthesising tight-binding TS inhibitors which would not be dependent on polyglutamation for antitumour activity. Addition of one glutamate residue on the γ-carboxyl of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583), i.e. dipeptide (1), resulted in stronger binding to TS by approximately 30-fold2. This finding was the starting point in our search for a tight TS inhibitor that could not be a substrate for FPGS. We report here the synthesis of 22 dipeptide and 6 γ-amide analogues of ICI 198583-γ-L-Glu.KeywordsAntitumour ActivityGlutamate ResidueProlonged RetentionPolyionic Nature2Zeneca PharmaceuticalThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.