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

Phenothiazine-based CaaX competitive inhibitors of human farnesyltransferase bearing a cysteine, methionine, serine or valine moiety as a new family of antitumoral compounds

“…This result is in accordance with previous reported studies which highlight the phenothiazine nucleus as well tolerated bulky unit for the A 2 binding site of human farnesyltransferase. 12,13,15 The 2-chloro substitution of the phenothiazine unit is tolerated, but does not improve the activity. Thus, methionine compound 1i has similar FTase affinity as unsubstituted derivative 1d (e.g., compound 1i: IC 50 (FTase) = 18.9 ± 3.2 lM vs compound 1d: IC 50 (FTase) = 11.7 ± 0.9 lM, Table 1).…”

Novel indolizine derivatives with unprecedented inhibitory activity on human farnesyltransferase

“…9,10 Our interest in anticancer therapy is to design, synthesize and evaluate new molecules targeting protein farnesyltransferase (FTase). [11][12][13][14][15] Protein farnesyltransferase (FTase) is a heterodimeric metalloenzyme of the prenyltransferase family. Farnesylation is a posttranslational modification of several cell signaling proteins such as small GTPases, including the oncogenic Ras proteins.…”

Synthesis and biological evaluation of a new class of triazin–triazoles as potential inhibitors of human farnesyltransferase

“…In order to block the activity of farnesyltransferase, we became interested in the design and the synthesis of FTIs bearing chelating units. Thus, after the successful investigation of compounds bearing complexing groups (CN, CO 2 R) that bind the zinc atom of protein farnesyltransferase [42], we describe here the study of compounds with a triazin-triazole unit as a potential zinc chelating moiety.…”

“…Therefore, it is necessary to design new farnesyltransferase inhibitors (FTIs) that specifically inhibit the farnesylation of target proteins involved in cell proliferation. In this field, our team already developed new families of human farnesyltransferase (FTase) inhibitors [42][43][44][45]. FTase is a heterodimeric metalloenzyme with two subunits: a (48 kDa) and b (45 kDa) [46].…”