Abstract
•G-11 is a novel trifluoromethyl-substituted pyrazole N-nucleoside showing strong and selective antiproliferative activities against various hematological and solid tumor cell lines.•G-11 induces cellular differentiation of the promyelocytic leukemia HL-60 cells to monocyte/macrophage and granulocyte.•G-11 inhibits the induced activation of the oncogenic kinase FLT3 (FMS-like tyrosine kinase 3, CD135), and thereby promotes differentiation of HL-60 cells.•In addition to the wild-type FLT3, G-11 also inhibits the constitutively active mutant type of FLT3 containing internal tandem repeats mutations (ITD).•Molecular Modeling studies show that G-11 docks within the ATP binding pocket of FLT3 in a comparable manner to the anticancer drug quizartinib, thus providing additional evidence supporting the development of G-11 as an anticancer agent for relapse free therapeutic strategies of AML patients.
Anticancer properties of chemically synthesized compounds have continuously been optimized for better efficacy and selectivity. Derivatives of heterocyclic compounds are well known to have selective antiproliferative effect against many types of cancer. In this study, we investigated the ability of an indigenously synthesized anticancer molecule, G-11 [1-(2”,3”,4”,6”-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3'-trifluoromethylphenylhydrazono)-3-trifluoromethyl-1,4-dihydropyrazol-5-one], to cause selective cytotoxicity and induce differentiation in the acute myeloid leukemia HL-60 cells. G-11 was able to exert cytotoxic effect on hematological (Jurkat, U937, K562, HL-60, CCRF-SB) and solid tumor (MCF-7, HepG2, HeLa, Caco-2) cell lines, with IC50 values significantly lower than noncancerous cells (HEK-293, BJ and Vero) and normal peripheral blood mononuclear cells. G-11 induced differentiation of HL-60 cells to granulocytes and monocytes/macrophages by inhibiting the activation of FLT3 (CD135 tyrosine kinase). ITD-FLT3 mutation found in many acute myeloid leukemia patients could also be targeted by G-11 as exhibited by its inhibitory effect on MOLM-13 and MV4-11 cell lines. Molecular docking studies suggest the involvement of Leu616, Asp698, Cys694 and Cys828 residues in binding of G-11 to FLT3. The ability of G-11 to cause selective cytotoxicity and induce differentiation in cancer cells could be clinically relevant for therapeutic gains.