Prodrugs of thymidylate synthase inhibitors: potential for antibody directed enzyme prodrug therapy (ADEPT)
Springer, C.J.; Bavetsias, V.; Jackman, A.L.; Boyle, F.T.; Marshall, D.; Pedley, R.B.; Bisset, G.M.
Anti-Cancer Drug Design 11(8): 625-636
1996
ISSN/ISBN: 0266-9536 PMID: 9022750 Document Number: 466694
Prodrugs of quinazoline antifolate thymidylate synthase (TS) inhibitors have been designed and synthesized for use in antibody-directed enzyme prodrug therapy (ADEPT). The syntheses of the alpha-linked dipeptides of two potent thymidylate synthase inhibitors, ZD1694 (N-(5-(N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)-L-glutamic acid) and ICI198583 (N-(4-(N-((2-methyl-3,4-dihydro-4-oxo-6-quinazolinyl)methyl)-N-prop-2-ynylamino)benzoyl)-L-glutamic acid) are described. The alpha-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 prodrugs were designed to be activated to their corresponding thymidylate synthase inhibitors at a turnout site by prior administration of a monoclonal antibody conjugated to the enzyme carboxypeptidase A (CPA). The viability of a colorectal cell line was monitored with the potential prodrugs in the presence or absence of CPA or with the parent drugs alone. All the dipeptides had greatly decreased cytotoxicity, with a deactivation of apprx 100-fold for the ZD1694 prodrugs and apprx 20-200-fold for the ICI198583 prodrugs. Activation of the alpha-linked L-alanine dipeptides with CPA led to a cytotoxicity enhancement of apprx 10-100 fold.