Author： Schlitzer M. Sattler I.
Publisher： Pharmaceutical Press
ISSN： 1460-8081
Source： Pharmacy and Pharmacology Communications, Vol.6, Iss.11, 2000-11, pp. : 507-512
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Abstract
We recently described non-peptidic, non-prenylic bisubstrate analogues as novel farnesyltransferase inhibitors comprising three modules—a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. In this study, we replaced the originally used β-alanyl linker with aminomalonic, aspartic and glutamic acid, respectively, to introduce a second functional group capable of complexing the essential zinc ion, located in the active site of farnesyltransferase.Apart from aminomalonic acid, all moieties showed reduced inhibitory activity. Interestingly, the benzyl esters of the aspartic and glutamic acid derivatives were more active than the free acids.The results provide further evidence for an additional lipophilic binding cleft in the active site of farnesyltransferase.
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