Synthesis and enzymatic activation of N-[ Nα-(4-amino-4-deoxypteroyl)- Nδ-hemiphthaloyl- l-ornithiny]- l-phenylalanine, a candidate for antibody-directed enzyme prodrug therapy (ADEPT)

N-[ N α-(4-Amino-4-deoxypteroyl)- N δ-hemiphthaloyl- l-ornithinyl]- l-phenylalanine ( 1), a carboxypeptidase A (CPA) cleavable prodrug was synthesized for use in an antibody directed strategy to improve the therapeutic selectivity of N α-(4-amino-4-deoxypteroyl)- N δ-hemiphthaloyl- l-ornithine ( 2),...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2002-03, Vol.10 (3), p.493-500
Main Authors: Wright, Joel E, Rosowsky, Andre
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases - antagonists & inhibitors
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Biological and medical sciences
Carboxypeptidases - metabolism
Carboxypeptidases A
Cattle
Cell Division - drug effects
Dipeptides - chemical synthesis
Dipeptides - metabolism
Dipeptides - pharmacology
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
General aspects
Humans
Inhibitory Concentration 50
Medical sciences
Pharmacology. Drug treatments
Prodrugs - chemical synthesis
Prodrugs - metabolism
Prodrugs - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured - drug effects
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Summary:N-[ N α-(4-Amino-4-deoxypteroyl)- N δ-hemiphthaloyl- l-ornithinyl]- l-phenylalanine ( 1), a carboxypeptidase A (CPA) cleavable prodrug was synthesized for use in an antibody directed strategy to improve the therapeutic selectivity of N α-(4-amino-4-deoxypteroyl)- N δ-hemiphthaloyl- l-ornithine ( 2), an extremely potent nonpoly-glutamatable DHFR inhibitor which is also highly cytotoxic. Compound 1 was shown by HPLC analysis to give a >99% yield of 2 upon incubation with bovine CPA (bCPA) for 20 min at 25 °C. In a spectrophotometric kinetic assay with 50 μM dihydrofolate as the competing substrate in the presence of 65 μM NADPH, 1+bCPA stoichiometrically inhibited recombinant human DHFR (rhDHFR) with a K i of 0.35 pM. In contrast, 1 without bCPA was a poor inhibitor of rhDHFR ( K i>10 μM). In a 72 h growth inhibition assay against cultured CCRF-CEM human leukemic lymphoblasts, the growth inhibitory activities of 1+bCPA, 2+bCPA, and 2 alone were the same (IC 50 1.3–1.4 nM), whereas 1 in the absence of bCPA was >100-fold less potent (IC 50 155 nM). Graphic
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(01)00298-X