New farnesyltransferase inhibitors in the phenothiazine series.
The biological screening of the chemical library of our Organic Chemistry Department, carried out on an automated fluorescence-based FTase assay, allowed us to discover that a phenothiazine derivative (1d) was an inhibitor of farnesyltransferase. Three new series of human farnesyltransferase inhibitors, based on a phenothiazine scaffold, were synthesized with protein farnesyltransferase inhibition potencies in the low micromolar range. Ester derivative 9d was the most active compound in these series. Four synthesized compounds were evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. The modest results obtained in this preliminary investigation showed that mixing the phenothiazine and the 1,2,3-triazole motif in the structure of a single compound can lead to new scaffolds in the field of farnesyltransferase inhibitors.
Department of Organic Chemistry, Al. I. Cuza University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania.
Dalila
D
Belei
Carmen
C
Dumea
Alexandrina
A
Samson
Amaury
A
Farce
Joëlle
J
Dubois
Elena
E
Bîcu
Alina
A
Ghinet
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010640:Phenothiazines; D051231:Farnesyltranstransferase; C031637:phenothiazine