Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives

W Pendergast; S H Dickerson; J V Johnson; I K Dev; R Ferone; D S Duch; G K Smith

doi:10.1021/jm00074a030

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives

J Med Chem. 1993 Oct 29;36(22):3464-71. doi: 10.1021/jm00074a030.

Authors

W Pendergast¹, S H Dickerson, J V Johnson, I K Dev, R Ferone, D S Duch, G K Smith

Affiliation

¹ Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.

PMID: 8230138
DOI: 10.1021/jm00074a030

Abstract

Several folate-like thymidylate synthase inhibitors are described in which the pteridine nucleus of the folic acid molecule is replaced by a benzoquinazoline moiety, which in turn is attached to the benzoylglutamate side chain by a sulfonamide link. The most potent compounds had Ki values as low as 2.5 nM against the human enzyme, were good substrates for the cellular reduced folate transport system and for folylpolyglutamate synthetase, and had IC50 values for growth inhibition of tumor cell lines as low as 70 nM.

MeSH terms

Glutamates / chemical synthesis
Glutamates / pharmacology
Glutamates / toxicity
Humans
Leukemia, T-Cell / drug therapy
Leukemia, T-Cell / metabolism
Peptide Synthases / antagonists & inhibitors
Quinazolines / chemical synthesis*
Quinazolines / pharmacology*
Quinazolines / toxicity
Sulfonamides / chemical synthesis
Sulfonamides / pharmacology
Sulfonamides / toxicity
Thymidylate Synthase / antagonists & inhibitors*
Tumor Cells, Cultured / drug effects

Substances

Glutamates
Quinazolines
Sulfonamides
Thymidylate Synthase
Peptide Synthases
folylpolyglutamate synthetase