Liming Hu

Copper-catalyzed synthesis of benzimidazoles via cascade reactions of o-haloacetanilide derivatives with amidine hydrochlorides

We have developed an efficient method for the synthesis of benzimidazoles via cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides. The protocol uses 10 mol % CuBr as the catalyst, Cs2CO3 as the base, and DMSO as the solvent, and no ligand is required. The procedure proceeds via the sequential coupling of o-haloacetoanilide derivatives with amidines, hydrolysis of the intermediates (amides), and intramolecular cyclization with the loss of NH3 to give 2-substituted 1H-benzimidazoles.

Electrochemically Initiated Oxidative Amination of Benzoxazoles Using Tetraalkylammonium Halides As Redox Catalysts

An electrochemically promoted coupling of benzoxazoles and amines has been developed, leading directly to the formation of 2-aminobenzoxazoles. The chemistry utilizes catalytic quantities of a tetraalkylammonium halide redox catalyst and is carried out under constant current conditions in a simple undivided cell. The use of excess chemical oxidant or large amounts of supporting electrolyte is avoided. This greatly simplifies the workup and isolation process and leads to a reduction in waste.

Environmentally Friendly Iron-Catalyzed Cascade Synthesis of 1,2,4-Benzothiadiazine 1,1-Dioxide and Quinazolinone Derivatives

We have developed an efficient iron-catalyzed method for the cascade synthesis of 1,2,4-benzothiadiazine 1,1-dioxide and quinazolinone derivatives. The protocol uses inexpensive and environmentally friendly FeCl(3) as the catalyst, and no ligand or additive was required. This is the first example of construction of nitrogen-containing heterocycles via iron-catalyzed N-arylation in the absence of ligand. Therefore, this method is of practical application for the synthesis of the two different nitrogen-containing heterocycles.

Electrochemical C–H functionalization and subsequent C–S and C–N bond formation: paired electrosynthesis of 3-amino-2-thiocyanato-α,β-unsaturated carbonyl derivatives mediated by bromide ions

An efficient paired electrosynthesis involving C–H functionalization and subsequent C–S and C–N bond formation for the assembly of valuable 3-amino-2-thiocyanato-α,β-unsaturated carbonyl derivatives has been developed. In the paired electrolysis, the amino and thiocyanato moieties originate from a single reagent or a combination of ammonium acetate and potassium isocyanate. The chemistry proceeds in a simple undivided cell employing a sub-stoichiometric amount of NH4Br that serves both as an inner sphere type redox catalyst and a supporting electrolyte; in this manner an additional conducting salt is not required. The reaction also works using a catalytic amount of NH4Br. Cyclic voltammetry and the results of control experiments demonstrate that the reaction proceeds via an anodically initiated C–H functionalization of the 1,3-dicarbonyl substrates that occurs via the electrochemical oxidation of bromide and simultaneous cathodic reduction of ammonium ions.

Electrochemical Oxidative Amination of Sodium Sulfinates: Synthesis of Sulfonamides Mediated by NH4I as a Redox Catalyst

An efficient protocol for the synthesis of sulfonamides via the electrochemical oxidative amination of sodium sulfinates has been developed. The chemistry proceeds in a simple undivided cell employing a substoichiometric amount of NH4I that serves both as a redox catalyst and a supporting electrolyte; in this manner additional conducting salt is not required. A wide range of substrates, including aliphatic or aromatic secondary and primary amines, as well as aqueous ammonia, proved to be compatible with the protocol. Scale-up was possible, thereby demonstrating the practicality of the approach. The electrolytic process avoids the utilization of external oxidants or corrosive molecular iodine and therefore represents an environmentally benign means by which to achieve the transformation.

Electrochemically initiated formation of sulfonyl radicals: synthesis of oxindoles via difunctionalization of acrylamides mediated by bromide ion

An efficient electrochemical approach for the synthesis of oxindoles has been developed from electrolysis of a mixture of sodium sulfinate and acrylamide. The chemistry avoids the utilization of additional conducting salt and proceeds in a simple undivided cell employing a catalytic amount of NH4Br (10 mmol%) as a redox catalyst. The protocol is practical, as proved by the one-pot, two-step procedure and scaled-up experiments. Mechanistic studies reveal that the electrochemical approach involves the formation of sulfonyl radicals via homolytic cleavage of in situ generated sulfonyl bromide.

Ergosterol peroxide activates Foxo3-mediated cell death signaling by inhibiting AKT and c-Myc in human hepatocellular carcinoma cells

Sterols are the important active ingredients of fungal secondary metabolites to induce death of tumor cells. In our previous study, we found that ergosterol peroxide (5α, 8α-epidioxiergosta-6, 22-dien-3β-ol), purified from Ganoderma lucidum, induced human cancer cell death. Since the amount of purified ergosterol peroxide is not sufficient to perform in vivo experiments or apply clinically, we developed an approach to synthesize ergosterol peroxide chemically. After confirming the production of ergosterol peroxide, we examined the biological functions of the synthetic ergosterol peroxide. The results showed that ergosterol peroxide induced cell death and inhibited cell migration, cell cycle progression, and colony growth of human hepatocellular carcinoma cells. We further examined the mechanism associated with this effect and found that treatment with ergosterol peroxide increased the expression of Foxo3 mRNA and protein in HepG2 cells. The upstream signal proteins pAKT and c-Myc, which can inhibit Foxo3 functions, were clearly decreased in HepG2 cells treated with ergosterol peroxide. The levels of Puma and Bax, pro-apoptotic proteins, were effectively enhanced. Our results suggest that ergosterol peroxide stimulated Foxo3 activity by inhibiting pAKT and c-Myc and activating pro-apoptotic protein Puma and Bax to induce cancer cell death.

Natural Endoperoxides as Drug Lead Compounds

Natural products, especially bioactive molecules as drug lead compounds, have attracted extensive attention in health promotion and in drug discovery and development. It is essential to understand the structures and functional mechanisms of these lead molecules prior to drug development. This review provides comprehensive information for more than 130 newly reported peroxides appeared in the literature in the recent years. The compounds are natural peroxides with bioactivities. While some of them appeared in previous reviews, a great number of newly-found natural peroxides with up-dated information are extensively reviewed in this article, which focuses on the biological activities based on various structural classes including monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids and steroidal peroxy compounds isolated from terrestrial and marine sources. These natural peroxides are valuable sources in drug discovery with antitumor and antimalarial activities.

Copper-catalyzed N-arylation and aerobic oxidative C–H/C–H coupling: one-pot synthesis of indoloimidazoquinoline derivatives

A novel and efficient copper-catalyzed one-pot synthesis of indoloimidazoquinoline derivatives has been developed. The protocol uses the readily available substituted 2-(2-bromophenyl)-1H-indoles, imidazole and benzoimidazoles as the starting materials, inexpensive CuBr as the catalyst, air as the terminal oxidant, and the procedure underwent a sequential copper-catalyzed intermolecular N-arylation and an aerobic oxidative intramolecular C–H/C–H coupling.

Novel morpholin-3-one fused quinazoline derivatives as EGFR tyrosine kinase inhibitors

A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFR(wt) kinase (IC50<1 μM). Compound a8 demonstrated the most potent inhibitory activity toward EGFR(wt) (IC50=53.1 nM). Compound a7 and a8 showed excellent inhibitory activities against mutant EGFR(T790M/L858R) and strong antiproliferative activity against H358 and A549 cell lines. Finally, molecular docking studies were performed to predict the possible binding mode of the target compounds. It is believed that this work would be very useful for designing a new series of tyrosine kinase inhibitors targeting EGFR.