Ag₂O-Induced Regioselective Huisgen Cycloaddition for the Synthesis of Fully Substituted Pyrazoles as Potential Anticancer Agents

Abstract

Efficient regioselective synthesis of novel fully substituted pyrazoles has been achieved through Huisgen cycloaddition reaction of δ-acetoxy allenoates with hydrazonoyl chlorides by the addition of Ag2O. The present approach offers the advantages of simpleness, high efficiency, mild conditions, wide substrate scope, and good-to-excellent regioselectivities. The strategy could be performed on a large-scale pattern to allow access to structurally versatile pyrazoles, of which a key intermediate of lonazolac (303), a nonsteroidal anti-inflammatory drug, could be synthesized efficiently. Moreover, several pyrazoles show obvious growth-inhibitory activity of Huh-7 cells, expected as potential anticancer agents.

Advances in the Synthesis of Heterocycles with Two and Three Heteroatoms using Hydrazonoyl Halides

“…Substituents such as R 1 = R 3 = H, R 2 = Me (43 %), R 1 = H, R 2 = Ph, R 3 = 2‐Me (52 %), R 1 = H, R 2 = Ph, R 3 =2‐naphtyl ( 50 %), R 1 = H, R 2 = Ph, R 3 =2‐furyl (40 %), R 1 = H, R 2 = Ph, R 3 =2‐thiophenyl (31 %), contributes to a significant reduction in the yield of heterocycles 200 . Cycloadducts showed good results of biological activity in preliminary experiments in relation to a cancer cell line [122] …”

“…Cycloadducts showed good results of biological activity in preliminary experiments in relation to a cancer cell line. [122] The reaction of hydrazonoyl chlorides 201 with monosubstituted allenes 202 in the presence of catalytic amounts of copper(I) chloride gives 1,3,5substituted pyrazoles 204 under mild conditions. This regioselective process proceeds through the initial formation of copper complex 203.…”

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

“…Xu et al prepared and characterized some new fully substituted pyrazoles and evaluated their growth inhibitory activity against Huh7 cells [ 151 ]. Among these, compound 150 demonstrated excellent cell growth inhibition even at different concentrations compared to doxorubicin.…”

“…Compound 129 exhibited the most potent inhibition against both cell lines with IC50 values of 10.89 and 15.60 µM, respectively, compared to 5-FU (IC50 = 26.75 and 32.75 µM). Xu et al prepared and characterized some new fully substituted pyrazoles and evaluated their growth inhibitory activity against Huh7 cells [151]. Among these, compound 150 demonstrated excellent cell growth inhibition even at different concentrations compared to doxorubicin.…”

“…Among these, compound 148 (IC50 = 10.2 µM) exhibited greater anticancer activity than the commercial anticancer drug 5-fluorouracil (IC50 = 23.1 µM) against A549. Meanwhile, compound 149 (IC50 = 12.4 µM) showed enhanced anticancer activity compared to Gefitinib (IC50 = 22.2 µM) against PC3.Xu et al prepared and characterized some new fully substituted pyrazoles and evaluated their growth inhibitory activity against Huh7 cells[151]. Among these, compound 150 demonstrated excellent cell growth inhibition even at different concentrations compared to doxorubicin.Otaibi et al synthesized four novel hybrid compounds bearing pyrazole and chalcone moieties and evaluated their ability to inhibit the in vitro proliferation of human lung (A549) and colon (Caco2) cancer cell lines[152].…”