A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.

The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo­[cd]­indol-2­(1H)-ones and pyrrolo­[4,3,2-de]­quinolin-2­(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.

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Diverse tetrasubstituted allenes are obtained selectively by the reaction of tert-propargylic alcohols and arylboroxines under rhodium catalysis. The reaction is assumed to proceed through an arylation/dehydroxylation process, which involves b-hydroxide elimination of a b-hydroxy alkenylrhodium intermediate that is generated by regioselective arylrhodation of the tert-propargylic alcohol. In addition, when enantioenriched propargylic alcohol was used to prepare optically active allene, high efficiency of central-to-axial chirality transfer was observed. The application of current method to structural modification of pharmaceutical drugs was also showcased by a highly diastereoselective transformation of mifepristone.

The first example of catalytic asymmetric conjugate alkynylation of β,γ-unsaturated α-ketoesters is reported. By using Rh(I)/(R)-DM-binap complex as the catalyst and diphenyl[(triisopropylsilyl)ethynyl]methanol as the alkynylating reagent, the alkynylation reaction proceeded smoothly to afford α-ketoesters bearing a propargylic chiral center at γ position in good yields with high enantioselectivities.