| Autor: |
T. C. Stephens, M. Brown, Ann L. Jackman, F. T. Boyle, L.R. Hughes, Z. S. Matusiak, R. Kimbell, A. M. Slater, M N Smith |
| Rok vydání: |
1993 |
| Předmět: |
|
| Zdroj: |
Advances in Experimental Medicine and Biology ISBN: 9781461362876 |
| DOI: |
10.1007/978-1-4615-2960-6_119 |
| Popis: |
ICI D1694, a quinazolinone based inhibitor of thymidylate synthase (TS) was developed to act in part through efficient metabolism to polyglutamates by the enzyme folypolyglutamyl synthetase (FPGS)1. The addition of γ-glutamates to agents such as ICI D1694 has two major consequences -the polyglutamates are up to 100-fold more active against isolated TS and the increased polyionic character results in intracellular retention leading to extended TS inhibition even after drug removal. In a cell line with altered expression levels of FPGS these classical agents have been shown to be less effective and cytotoxicity then generally correlates with TS inhibitory activity.(See accompanying paper A.L.Jackman et al.). In our search for agents to compliment ICI D1694, we therefore wanted compounds which were potent inhibitors of TS, used the reduced folate / methotrexate carrier (RFC) for cell entry but did not depend on intracellular polyglutamation for activity. Because of its excellent TS inhibitory activity we chose 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)2 as the basis of this investigation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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