PRODRUGS OF THYMIDYLATE SYNTHASE INHIBITORS - POTENTIAL FOR ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT)

Prodrugs of quinazoline antifolate thymidylate synthase (TS) inhibitor s have been designed and synthesized for use in antibody-directed enzy me prodrug therapy (ADEPT). The syntheses of the alpha-linked dipeptid es of two potent thymidylate synthase inhibitors, ZD1694 ,4-dihydro-2- methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl]-L-glutam ic acid} and 1CI198583 methyl-3,4-dihydro-4-oxo-6-quinazolinyl)methyl] -N- prop-2-ynylamino]benzoyl]-L-glutamic acid} are described. The alph a-carboxyl of the glutamic acid has been linked through an amide bond to an L-alanine or an L-glutamic acid. The alpha-linked L-dipeptide pr odrugs were designed to be activated to their corresponding thymidylat e synthase inhibitors at a tumour site by prior administration of a mo noclonal antibody conjugated to the enzyme carboxypeptidase A (CPA). T he viability of a colorectal cell line was monitored with the potentia l prodrugs in the presence or absence of CPA or with the parent drugs alone. Al the dipeptides had greatly decreased cytotoxicity, with a de activation of similar to 100-fold for the ZD1694 prodrugs and similar to 20-200-fold for the 1CI198583 prodrugs. Activation of the alpha-lin ked L-alanine dipeptides with CPA led to a cytotoxicity enhancement of similar to 10-100-fold.