13C-labeled compounds are invaluable in drug discovery as lead compounds and as tracers for studying drug bioavailability and pharmacodynamics. However, these approaches are mainly limited to high-value chemical labeling materials and low atom economy multistep synthesis. Herein, we report a highly efficient Pd-catalyzed reductive carbonylation method for the synthesis of 13C-labeled flavones using near-stoichiometric [13C]CO2. With aromatic alkynes, aliphatic alkynes and substituted 2-iodophenols as the reaction partners, the corresponding 13C-labeled flavones were obtained in good yields with excellent functional group tolerance. Mechanistic studies suggest that the phenolic group accelerates CO2 mass transfer, followed by intramolecular migration and the formation of key acylpalladium intermediates. Notably, para-tBu substituted 13C-flavone results in a more pronounced enhancement of antitumor efficacy compared to ester or OMe substitutions, relative to their 12C analogs.

Carbazole moiety exhibits excellent electron transfer ability due to its rigid planar structure and large conjugate system.The N atom and aromatic ring of carbazole can be easily modified,and carbazole-based ligands and polymers have attracted significant amounts of interests in the fields of catalysis and material sciences.Important progress has been achieved in both homogeneous and heterogeneous catalysis promoted by catalysts containing carbazole as the backbone or linker.The catalytic conversion of carbon dioxide can provide an important technology support for realization of carbon neutrality goals.In this paper,the recent progresses on the use of carbazole-based ligands,carbazole-based complexes or carbazole-based het-erogeneous materials in catalytic transformation of CO2 are reviewed,including the methods of catalyst preparation,the dif-ferent types of reactions in homogeneous and heterogeneous catalysis.This review will provide systematic information for further understanding the important role of carbazole units in catalysis and designing more efficient carbazole-based materials.

Polar solvents are often chosen for transition metal catalyzed C-N coupling reactions. In this work, it was found that the use of alkane solvents (e.g. cyclohexane, heptane) allows for highly efficient Ni-catalyzed C-N coupling of aryl pseudohalides with different types of amines in the presence of NHC ligands. Excellent functional group tolerance was achieved. Stronger hydrogen bonding effect between amine NH moiety and polar OTs/OTf in alkane solvents might be responsible for the high activity. Meanwhile, some of the obtained products showed in vitro antiproliferative activities.

Carbazole derived phosphine ligands containing pyridine moiety were designed and prepared. It allows the challenging Pd-catalyzed Markovnikov-selective alkoxycarbonylation of aliphatic alkenes to give the branched ester products (28 examples; 51–97% branch selectivity). Preliminary mechanistic studies support that the bridging bromide between Pd and Mn centers is crucial for the enhancement of regioselectivity.

An efficient method has been developed for the reductive amination of CO2 by using readily available and recyclable oxofluorovanadates as catalysts. Various amines are transformed into the desired N-formylated products in moderate to excellent yields at room temperature in the presence of phenylsilane. Mechanistic studies based on in situ infrared spectroscopy suggest a reaction pathway initiated through F-Si interactions. The activated phenylsilane allows for CO2 insertion to produce phenylsilyl formate, which undergoes attack by the amine to generate the target product.

The first example of borate-catalyzed N-formylation of amines using CO2 as the carbon source in the presence of hydrosilanes is demonstrated using sodium (trihydroxy)phenylborate as a transition metal-free catalyst.

Ortho-selective aromatic C-H functionalization is frequently used in organic synthesis and chemical/pharmaceutical industries. However, this reaction relies heavily on the use of directing groups suffering from limited substrate scope and extra steps to put on and remove the directing/protecting groups. Herein we present the previously neglected concept that enables good to nearly complete selective ortho position. Proton transfer was utilized to tune the electron density on the aryl ring and determine the positional selectivity of electrophilic substitution. Consistently with deuteration experiments and DFT studies, this work demonstrates that acid-promoted proton transfer directs accelerated ortho-selective halogenation of NH/OH contained aromatic amines/phenols with excellent selectivity (>40 examples; up to 98:2 ortho/para selectivity). The application potential of this Fe-catalyzed method is demonstrated by the convenient synthesis of three alkaloids and tizanidine. This report raises the possibility that proton transfer could serve as the basis of developing new selective C-H functionalization reactions.

Functionalization of amines by using CO2 is of fundamental importance considering the abundance of amines and CO2 . In this context, the catalytic formylation and methylation of amines represent convenient and successful protocols for selective CO2 utilization as a C1 building block. This study represents the first example of selective catalytic double N-formylation of aryl amines by using a dinuclear Mn complex in the presence of phenylsilane. This robust system also allows for selective formylation and methylation of amines under a range of conditions.

The presence of different aldehydes is found to have a significant influence on the catalytic performance when using PN(H)P type ligands for dehydrogenation of alcohols. Accordingly, hybrid multi-dentate ligands were discovered based on an oxygen-transfer alkylation of PNP ligands by aldehydes. The relevant Ru-PNN(PO) system provided the desired unsymmetrical esters in good yields via acceptorless dehydrogenation of alcohols. Hydrogen bonding interactions between the phosphine oxide moieties and alcohol substrates likely assisted the observed high chemoselectivity.

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.

Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.

Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 μM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 μM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4.