Synthesis and biological evaluation of a new series of phenothiazine-containing protein farnesyltransferase inhibitors

• Published in: European journal of medicinal chemistry 2013-01, Vol.59, p.101-110
• Main Authors: Abuhaie, Cristina-Maria, Ghinet, Alina, Farce, Amaury, Dubois, Joëlle, Gautret, Philippe, Rigo, Benoît, Belei, Dalila, Bîcu, Elena
• Format: Article
• Language: English
• Subjects: Anticancer agent; Catalytic Domain; Chemical Sciences; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fanesyltransferase inhibitors; Farnesyltranstransferase - antagonists & inhibitors; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Organic chemistry; Phenothiazine; Phenothiazines - chemistry; Phenothiazines - pharmacology; Pyridin-(1H)-ylidene; Ylide
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.11.008

Two new families of human farnesyltransferase inhibitors 13a–m and 14a–d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC50 values of 0.7 and 0.6 μM, respectively. [Display omitted] Two new families of human farnesyltransferase inhibitors 13a–m and 14a–d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC50 values of 0.7 and 0.6 μM, respectively. ► Synthesis and evaluation of phenothiazine-containing farnesyltransferase inhibitors. ► Synthesis of new ylides with biological potential. ► Unexpected compounds were synthesized from 2- and 4-picolinium salts. ► Discovery of pyridin-(1H)-ylidene derivatives with IC50 values in the low submicromolar range. ► Study of the generalization of the synthesis of pyridin-(1H)-ylidene derivatives.