Design and synthesis of new potent anticancer pyrazoles with high FLT3 kinase inhibitory selectivity

Abstract

A new series of 1H- and 2H-pyrazole derivatives (35 final compounds) has been designed and synthesized in this study. A selected group (13 compounds) was then tested over a panel of 60 cancer cell lines at a single dose concentration of 10microM. At this concentration, six compounds have showed moderate to strong mean inhibitions, and were further tested at five-dose testing mode to determine their IC(50) over the 60 cell lines. The IC(50) values of the tested compounds indicated high potency (as for compound 10f) as well as high efficacy (as for compound 11e). Accordingly, compound 10f was then tested at a single dose concentration of 10microM over a panel of 54 kinases to determine its kinase inhibitory profile. The compound has showed good selectivity towards FLT3 kinase, associated with a moderate potency, with an IC(50) value of 1.74microM.

Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines

“…We also investigated the effect of CF 3 substituent on (pyridine-2-yl)piperazines. The (3-CF 3 -pyridin-2-yl) piperazine (4c) resulted in a better cytotoxicity against MCF7 cells Recent studies have shown several diarylpyrazole derivatives resembling the general structure of present work possess ALK5, FLT3, ERK and B-raf kinase inhibitory activities suggesting that the kinase inhibition may play a role for the observed cytotoxicity of present compounds [12e15, 20,21]. Therefore, in order to investigate the mechanism of action, and the kinase inhibitory profile of this new class of compounds, compound 4j with the highest potency on all cancer cell lines was tested at a single dose concentration of 10 mM over a panel of 140 kinases (Table S1, Supporting Material) using a radioactive ( 33 P-ATP) filter-binding assay at International Center for Kinase Profiling (University of Dundee, Scotland).…”

Design and synthesis of novel phenylaminopyrimidines with antiproliferative activity against colorectal cancer

“…The synthesis of the target compounds started with the key ester methyl 3-methoxy-5-methylbenzoate (4), which was prepared following reported procedures. 16 As showed in Scheme 1, the benzoate ester 4 underwent a nucleophilic attack at its carboxylate carbon by the activated methylene group of 2-chloro-4methylpyridine. The activation of this methyl group into an active methylene was achieved by the dropwise addition of lithium bis(trimethylsilyl)amide (LHMDS) in dry THF at room temperature.…”

“…In this study, we further modied the structure of this anticancer lead through extended substitution at the pyridin-4-yl ring. A variety of substituted and unsubstituted aromatic structures have been attached to this point of the molecule through a series of Suzuki coupling reactions 16,17 in order to properly evaluate the effect of this extended substitution on compound's activity (Fig. 2).…”

Synthesis and comparative study between two pyrazoles in inhibition against the corrosion of steel in 1 M hydrochloric acid

“…Pyrazoles are an important class of heterocyclic compounds. They are used in several domains of current research; for example, we found pyrazole derivatives with biological activities such as antitumor [1,2], antibacterial [3], anticancer [4], antidiabetic agent [5], anti-inflammatory [6], antidepressant [7], antimalaria [8],anticonvulsant [9], antituberculosis [10] and antiviral activities [11].…”