Quinazoline Antifolate Thymidylate Synthase Inhibitors: Replacement of Glutamic Acid in the C2-Methyl Series
| Autor: | R. Kimbell, Andrew John Barker, Marsham Pr, Alan Hilary Calvert, Pegg Sj, F. T. Boyle, Ann L. Jackman, O'Connor Bm, Leslie Richard Hughes, Wardleworth Jm |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
chemistry.chemical_classification
Chemistry Stereochemistry Glutamic Acid Antineoplastic Agents Thymidylate Synthase Glutamic acid Amino acid Mice Structure-Activity Relationship chemistry.chemical_compound Folic Acid Amide Drug Discovery Quinazolines Tumor Cells Cultured Lactam Quinazoline Animals Folic Acid Antagonists Molecular Medicine Moiety Azide Leukemia L1210 Quinazolinone |
| Zdroj: | Journal of Medicinal Chemistry. 38:994-1004 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00006a019 |
| Popis: | The synthesis of a series of analogues of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (ICI 198583, 1) is described in which the glutamic acid residue has been replaced by other alpha-amino acids. Most of these analogues were prepared by coupling of tert-butyl-4-(prop-2-ynylamino)benzoate (37) with 6-(bromomethyl)-3,4-dihydro-2-methyl-4-oxoquinazoline (34) followed by deprotection of the tert-butyl ester to the acid and azide-mediated coupling to the appropriate amino acid or amino acid ester. In cases where the amino acid ester was unreactive with the acid azide, a modification was used in which the quinazolinone moiety was protected as its 3-(pivaloyloxy)methyl derivative. This permitted the generation of the more reactive acid chloride of the p-aminobenzoate unit. In general these modifications result in compounds that have equivalent potency to 1 as inhibitors of isolated TS except where the amino acid lacks a lipophilic alpha-substituent. These compounds appear to require the reduced folate carrier (RFC) for transport into cells, but since they are not converted intracellularly into polyglutamated forms, they have a lower level of cytotoxicity compared to 1. The removal of the alpha-carboxylic acid has given a second set of analogues of 1 which contain simple alkyl amide, benzyl, substituted benzyl, and heterocyclic benzyl amide derivatives. These are considerably less potent than 1 as TS inhibitors but display 1-10 microM cytotoxicities due to the fact that they do not require RFC transport and can presumably readily enter cells by passive diffusion through the cell membrane. Molecular modeling and NMR studies indicated that the incorporation of, respectively, 7-methyl and 2'-fluoro substituents would favor the optimum conformation of these molecules for interaction with the TS enzyme. Accordingly, these substituents were incorporated into selected examples to give the series of analogues 47-55. These all show enhanced (approximately 10-fold) inhibition of TS compared to their unsubstituted counterparts. In the substituted benzylamides (51, 52) and heterocyclic benzyl amides (53-55) the ability to enter cells by passive diffusion results in highly potent (1 microM) cytotoxic agents. |
| Databáze: | OpenAIRE |
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