Green synthesis of a new series of pyroglutamides targeting human farnesyltransferase

Pyroglutamide derivatives have emerged as promising inhibitors of human farnesyltransferase (FTIs), an important target in oncology and also in rare diseases such as Hutchinson-Gilford progeria syndrome (HGPS). This report describes the chemical efforts to enrich the pyroglutamide series using greener and recyclable catalysts. The central reaction studied was an amidation between methyl pyroglutamates or vinylogues and amines. Ten catalysts have been tested in this amidation reaction: two classical Lewis acids (ZnCl2, ZrCl4), four impregnated montmorillonite K10 with ZnCl2 namely Cat1, Cat2, Cat3 and Cat4 (not activated, activated at 120 °C, 280 °C and 500 °C, respectively) and four montmorillonites K10 (commercial montmorillonite K10 not activated, activated at 120 °C, 280 °C and 500 °C). The most efficient catalyst was Cat4. The recyclability of Cat4 over five synthesis runs has been successfully tested. Twenty-six amides were synthesized and screened for their potential to inhibit human farnesyltransferase. Four points of chemical modulation around the pyrrolidine-2-one ring have been realized allowing to complete structure-activity relationships in these series. The study revealed several potent inhibitors targeting human farnesyltransferase in vitro with IC50 values in the submicromolar range and down to 30 nM. The docking of compounds in the active site of FTase highlighted that the S-isomers of pyroglutamides had good affinity. This study propels pyroglutamide derivatives as promising candidates for future functionality assays and in vivo evaluation.