ABSTRACT
A new family of CaaX competitive inhibitors of human farnesyltransferase based on phenothiazine and carbazole skeleton bearing a l-cysteine, l-methionine, l-serine or l-valine moiety was designed, synthesized and biologically evaluated. Phenothiazine derivatives proved to be more active than carbazole-based compounds. Phenothiazine 1b with cysteine residue was the most promising inhibitor of human farnesyltransferase in the current study.
Subject(s)
Amino Acids/metabolism , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Phenothiazines/pharmacology , Amino Acids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cysteine/chemistry , Cysteine/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase/metabolism , Humans , Methionine/chemistry , Methionine/metabolism , Molecular Structure , Phenothiazines/chemical synthesis , Phenothiazines/chemistry , Serine/chemistry , Serine/metabolism , Structure-Activity Relationship , Valine/chemistry , Valine/metabolismABSTRACT
Novel phenothiazine derivatives bearing an amino acid residue were synthesized via peptide chemistry, and evaluated for their inhibitory potential on human farnesyltransferase. The phenothiazine unit proved to be an important bulky unit in the structure of the synthesized inhibitors. Propargyl ester 20 bearing a tyrosine residue exhibited the best biological potential in vitro in the present study. Further syntheses and biological evaluation of phenothiazine derivatives are necessary in order to gain a full view of SAR in this family of farnesyltransferase inhibitors.
