Chiral copper complex bearing binaphthyl-prolinol-imidazoline type tridentate ligand was effective in enantioselective Friedel-Crafts alkylation of indoles with cyclic N-sulfonyl ketimino esters. The catalyst system exhibited excellent catalytic activity (up to 95 % yield) and enantioselectivity (up to 96 % ee), affording a series of chiral cyclic alpha-amino acid ester derivatives under mild reaction conditions. In addition to different indoles, the catalyst system was also compatible with pyrrole and 1-naphthol. The scalability of the reaction was exemplified with a gram-scale reaction. A plausible reaction mechanism was proposed based on preliminary DFT calculation results.

The Cu(II)-catalyzed remote enantioselective addition of 3-cyano-4-methylcoumarins to tryptanthrin-derived N-Boc ketimines is reported. The protocol tolerates variations in both the tryptanthrin and cyanomethyl coumarin parts, and the corresponding products are obtained with up to 99% ee and up to 96% yield. In addition to stereofacial selective activation of ketimines, the catalyst should also meet the steric demand of the nucleophiles to achieve high levels of enantioselectivity. A gram-scale reaction was possible, and X-ray diffraction confirmed the absolute configuration of the products. Moreover, the derivatization reaction of the product proceeded smoothly.

Enantioselective additions of thiols and thiophenols to pyrazolinone-derived ketimines were realized using a Ni(II) complex bearing a tridentate binaphthyl-proline-imidazoline-based chiral ligand as the catalyst. The well-defined confined environment of the catalyst enabled the stereofacial selective activation of the electrophiles, and the products were obtained in up to 99% yield with 99% ee. The reactions featured low catalyst loading, mild conditions, broad substrate scope, and gram-scale utility. X-ray diffraction experiments confirmed both the configuration of the C═N double bond and the absolute configuration of the products, and stereofacial selection of the reactions was deduced accordingly.

Construction of biologically interesting tryptanthrin-derived N,O-ketals was enabled via Cu(II)-catalyzed enantioselective addition of alcohols and tert-butyl hydroperoxide to tryptanthrin-derived N-Boc ketimines. Stereoselective activation of the electrophiles was possible using structurally confined chiral catalysts although such electrophiles suffered from the drawbacks such as low reactivity or steric hindrance around the reaction center. The protocol tolerated variations in both the tryptanthrin part and the alcohol scopes, and the products could be obtained with up to 99% ee and in up to 99% yield. Gram-scale reaction was possible, and functional group transformations could also be realized. X-ray diffraction experiments confirmed the configuration of tryptanthrin-derived N-Boc ketimine as well as the absolute configuration of the product.

A new type of proline-based chiral ligands were designed and prepared starting from 8-hydroxy-2-methylquinoline and derivatization of L-proline. Coupling of these two parts yielded the desired chiral ligands in good isolated yields. The performance of these chiral ligands was evaluated using enantioselective addition of diethylzinc to aromatic aldehydes as model reactions. Under the optimized conditions, enantioselective addition of diethylzinc to aromatic aldehydes proceeded readily, giving the desired chiral alcohols in high yields and up to 97 % ee's.

By fine-tuning the electronic and steric properties of the chiral ligands, chiral Cu(II) complex-catalyzed enantioselective Friedel-Crafts alkylation/lactonization of 1-naphthols and electron-rich phenols with trifluoropyruvates provided the desired products with up to 99% ee and up to 99% yield. The reactions were carried out on a gram scale with low catalyst loading. Especially, the optically pure GABAB positive allosteric modulator (R)-BHFF was prepared using this protocol.

Herein, we synthesized new 3D flower-like boron doped PtCe nanoalloys formed by nanosheets with ultra-thin thickness (B-PtCe NSs) using a convenient one-pot method without any surfactants. The self-supporting 3D architecture overcomes the commonly closely packed and overlapping problems of conventional 2D nanosheets. The ultrathin feature of the petals provides large active areas, facilitating mass and electron transfer rates. Specifically, the synergistic effect between different components effectively modifies the electronic structures and upshifts the d-band center. The B-PtCe NSs therefore exhibited superior electrocatalytic performances to methanol and ethanol oxidation reactions (MOR/EOR). Specifically, the mass/specific activities of B-PtCe NSs were 2.75 +/- 0.050 A.mg(Pt)(-1)/27.58 +/- 0.50 A m(-2), which are 3.85/2.12 times higher than those of commercial Pt/C catalysts (0.71 +/- 0.011 A.mg(Pt)(-1)/12.96 +/- 0.20 A m(-2)) toward MOR, respectively. The ultrathin B-PtCe NSs also exhibited superior mass/specific activity of 2.12 +/- 0.04 A.mg(Pt)(-1)/21.11 +/- 0.40 A m(-2) to EOR. Furthermore, the B-PtCe NSs exhibit higher electrocatalytic stability owing to their special morphological feature and promoted anti-CO properties. More importantly, the B-PtCe also demonstrates superior mass activities of 0.159, 0.851, 2.23, and 2.71 A.mg(Pt)(-1) to the electrooxidation reactions of glucose, isopropanol, glycerol, and ethylene glycol, respectively. We also unraveled the improved mechanism though density functional theory calculations.

1,2,3-Triazole skeleton may act as both a hydrogen bond acceptor and a linker connecting different structures, and androgens bearing 1,2,3-triazole structures exhibit interesting biological activities against prostate cancer. Based on this rationale, various substituted 1,2,3-triazole groups were introduced to stanolone via click chemistry, and a total of 32 stanolone derivatives (13a - 13r and 14a-14n) were obtained under mild conditions. Their in vitro inhibitory activities against two prostate cancer cell lines, PC3 and DU145, were evaluated, and a preliminary structure-activity relationship (SAR) was established. Compounds 14e, 14f, and 14 k exhibited significant inhibitory effects, with IC50 values of 12.33 μM, 6.69 μM, and 13.83 μM, respectively, against PC3 cells, and 18.55 μM, 5.67 μM, and 5.08 μM, respectively, against DU145 cells. These compounds were found to induce mitochondrial apoptosis in PC3 and DU145 cells. Further investigation revealed the activation of the γ-H2AX signaling pathway, leading to DNA damage in tumor cells. Notably, compound 14 k also demonstrated promising antitumor efficacy in a DU145 xenograft mouse model, and showing no cytotoxicity to normal human renal epithelial cells (HK-2), human liver cells (LO2), or human lung epithelial cells (BESA-2b) in vitro, indicating its potential as a lead compound for future antitumor drug study.

Cu(II)-complex-catalyzed enantioselective Friedel-Crafts alkylation of aniline derivatives with 4-benzylidenepyrrolidine-2,3-dione-type electrophiles was enabled, and the desired products were obtained with up to 96% ee. Both N-mono- and N,N-dialkylated anilines and related compounds could be used as nucleophiles, and the reaction at gram scale also proceeded readily, providing the desired product without the loss of enantiomeric excess. The high enantioselectivity of the reaction relied on the unique structure of the chiral catalysts, which allowed the effective and stereofacially selective activation of the substrates. X-ray diffraction experiment confirmed the absolute configuration of the product, and stereofacial selection of the reactions was deduced based on this result.

New chiral ligands could be obtained by introducing proline moieties and imidazoline moieties to binaphthyl skeletons. The chiral ligands exhibited balanced rigidity and flexibility which could allow the change of the conformations during the reactions on one hand, and could provide sufficient asymmetric induction on the other. The proline moiety could act as a linker connecting the binaphthyl skeletons and the imidazoline moieties as well as a coordinating group for the central metal, and the electronic and steric properties of the imidazoline groups could be carefully fine-tuned by the use of different substituents. In the presence of Cu(II) catalyst bearing such chiral ligands, aza-Friedel-Crafts reaction of 1-naphthols and electron-rich phenols with isatin-derived ketimines provided the desired products with good to excellent yields and up to 99 % ee. The reactions showed good scalability, and excellent ee could still be obtained when the reaction was carried out in gram-scale. Products with up to 99 % yield and up to 99 % ee were obtained in aza-Friedel-Crafts reaction of 1-naphthols and electron-rich phenols with isatin-derived ketimines using Cu(II) complex bearing binaphthyl-proline-imidazoline-based tridentate chiral ligand as catalyst. The system showed good scalability, and reaction carried out in gram-scale also provided the desired product in excellent ee. image

Modification of marketed drugs is an important way to develop drugs because its safety and clinical applicability. Oxygen-nitrogen heterocycles are a class of important active substances discovered in the process of new drug development. Dolutegravir, an HIV drug with a nitrogen-oxygen heterocycle structure, has the potential ability to inhibit cell survival. In order to find and explore novel anti-tumor drugs, new dolutegravir derivatives bearing different 1,2,3-triazole moieties were prepared via click reactions. In vitro biological experiments performed in several lung cancer cell lines suggested that these novel compounds displayed potent anti-tumor ability. Especially, the compound 9e with a substituent of 2-methyl-3-nitrophenyl and the compound 9p with a substituent of 3-trifluoromethylphenyl were effective against PC-9 cell line with IC50 values of 3.83 and 3.17 µM, respectively. Moreover, compounds 9e and 9p were effective against H460 and A549 cells. Further studies suggested that compounds 9e and 9p could induce cancer cell apoptosis in PC-9 and H460, inhibit cancer cell proliferation, change the cell cycle, and increase the level of reactive oxygen species (ROS) which further induce tumor cell apoptosis. In addition, compounds 9e and 9p increased LC3 protein expression which was the key regulator in autophagy signaling pathway in PC-9 cells. Compound 9e also showed low toxicity against normal cells, and could be regarded as an interesting lead compound for further structure optimization.

Aldose reductase2 (ALR2), an activated enzyme in polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for diabetic complications especially in diabetic peripheral neuropathy (DPN). However, lots of ALR2 inhibitors showed serious side-effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c carrying carbonyl group at the 3-position of thiadiazine ring showed high potent inhibition against ALR2 (IC50 = 33.19 nM) and about 16109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated 15c had a good pharmacokinetic feature (T1/2 = 5.60 h, AUC(0-t) = 598.57±216.5 μg/mL*h), which was superior to Epalrestat (T1/2 = 2.23 h, AUC(0-t) = 20.43±3.7 μg/mL*h). Finally, in streptozotocin (STZ)-induced diabetic rat model, 15c significantly increased the nerve conduction velocities (NCVs) of impaired sensory and motor nerve, achieved potent inhibition of D-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold (PWMT). Combined the above investigations, we proposed that 15c might represent a promising lead compound for discovery of anti-diabetic peripheral neuropathy drug.

Herein, we grew in situ Co-incorporated NiOSO4-NiMoO4 heterostructures on nickel foam (Co-NiSMoO/NF). The introduction of S2- and MoO42- into CoNi-ZIF precursor leads to the compositional and electronic reconstruction, resulting in the Co-NiSMoO/NF nanostructures. The attractive features in the morphology, composition, and electronic structure cooperatively endow them with high electrocatalytic performances. As a result, the Co-NiSMoO/NF nanostructures exhibit superior electrocatalytic performances to oxygen evolution, urea oxidation, and thus overall water/urea splitting reactions (OER/UOR/OWS/OUS). Specifically, the Co-NiSMoO/NF shows a high electrocatalytic OER activity, with low overpotentials of 172 mV@10 mA cm-2, 238 mV@20 mA cm-2, 278 mV@50 mA cm-2, 308 mV@100 mA cm-2 in alkaline. For UOR, the overpotential is just as low as 1.318 V@10 mA cm-2, 1.330 V@20 mA cm-2, 1.346 V@50 mA cm-2, and 1.401 V@100 mA cm-2. Especially, the voltage of the record cell even drops to 1.446 V@10 mA cm-2 to OUS. Furthermore, the Co-NiSMoO/NF electrocatalysts still stable to OER, UOR, and OUS even for up to 100 h. More importantly, we also realized H2 production in a green manner driven by solar. Under solar illumination on a solar panel, H2 production speed is even as high as 408 L h-1 m-2.

Acute lung injury (ALI) is a respiratory failure disease associated with high mortality rates in patients. The primary pathological damage is attributed to the excessive release of pro-inflammatory mediators in pulmonary tissue. However, specific therapy for ALI has not been developed. In this study, a series of novel ferulic acid-parthenolide (FA-PTL) and ferulic acid-micheliolide (FA-MCL) hybrid derivatives were designed, synthesized, and evaluated for their anti-inflammatory activities in vitro. Compounds 2, 4, and 6 showed pronounced anti-inflammatory activity against LPS-induced expression of pro-inflammatory cytokines in vitro. Importantly, compound 6 displayed good water solubility, and treatment of mice with compound 6 (10 mg/kg) significantly prevented weight loss and ameliorated inflammatory cell infiltration and edema in lung tissue, as well as improving the alveolar structure. These results suggest that compound 6 (((1aR,7aS,8R,10aS,10bS,E)-8-((dimethylamino)methyl)-1a-methyl-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 2-hydroxypropane-1,2,3-tricarboxylate) might be considered as a lead compound for further evaluation as a potential anti-ALI agent.

Here, we demonstrated a copper(II)-catalyzed enantioselective addition of aryl amines to isatin-derived N-Boc-ketimines using chiral O-N-N tridentate ligands derived from BINOL and proline. Generally, the chiral acyclic N,N'-ketals were obtained in high yields (up to 98%) and excellent ee values (up to 98%). Various aryl amines could be tolerated and a gram-scale reaction was also possible. Further, an X-ray diffraction experiment confirmed that the configuration of isatin-derived N-Boc ketimine should be (Z). Confirmation of the configuration of the ketimine would make it easier to understand the rationale for stereofacial selective activation of the electrophile with either organo- or Lewis acid-based catalysts.

Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5S-heudelotinone (an enantiomer) as a potent agent against experimental colitis that acts by modulating the gut microbiota. 5S-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids (SCFAs); thus, it regulates the intestinal immune system by reducing proinflammatory immune cell numbers, and maintains intestinal mucosal integrity by modulating tight junctions (TJs). Moreover, 5S-heudelotinone (2) ameliorates colitis-associated colorectal cancer (CAC) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced in situ carcinoma model. Together, these findings reveal the potential of a novel natural product, namely, 5S-heudelotinone, to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.

Transition metal complex-catalyzed enantioselective aza-Friedel-Crafts alkylation of ketimines with aniline derivatives has been problematic due to the relatively low reactivity of these reactants. Herein, we will show that using structurally confined Ni(ii) complexes as the catalysts, the reaction mechanism of the aza-Friedel-Crafts reactions was altered and highly efficient asymmetric aza-Friedel-Crafts alkylations of anilines with cyclic N-sulfonyl alpha-ketiminoesters were realized. In the presence of 0.1-0.5 mol% of nickel complex bearing structurally confined binaphthyl-proline-imidazoline-based chiral ligand L8, the reactions proceeded smoothly under mild conditions, affording the desired alpha-quaternary amino esters in up to 96% yield with up to 99% ee. Both N,N-disubstituted and N-monosubstituted aniline derivatives were tolerated in the transformations. Gram-scale reaction and functional group transformations of the product have been achieved. Preliminary DFT and isotope effect studies suggest that, unlike the traditional Friedel-Crafts alkylations of aromatic compounds in which the electrophilic attack on the aryl rings is the key step, aromatization of the aza-Friedel-Crafts intermediate also plays a key role in achieving high enantioselectivity in the reactions.

Highly enantioselective Friedel-Crafts reactions of indoles with isatins were realized using chiral Cu(I) catalyst bearing BINOL and proline-based electronically and sterically tunable chiral O-N-N tridentate ligands. Such catalyst system showed excellent performance in enantioselective Friedel-Crafts alkylation of different indoles, and a series of 3-indolyl-3-hydroxyoxindoles were obtained in high yields (90-98 %) and excellent enantioselectivities (82-98 % ee) under mild reaction conditions.

A mild and efficient catalyst system for asymmetric Friedel-Crafts alkylation of indoles with trifluoropyruvates was reported. The chiral ligands took the advantages of both the proline and the binaphthyl moieties, and the in situ prepared Cu(II) catalyst showed good substrate tolerance in the reactions. Indoles bearing different substituents could be tolerated, and the desired products could be obtained in up 99 % yields and up to 98 % ee. Especially, the reactions could be carried out in gram scale without the loss of stereoselectivity, and some of products were able to achieve 99 % ee after simple crystallization.

Using binaphthyl-proline-based chiral ligands, Zn(II)-catalysed addition of alcohols and tert-butyl hydroperoxide to isatin-derived N-Boc ketimines provided the isatin-derived C3 N,O-aminals in up to 99% yield and up to 99% ee. The reactions could be carried out under mild conditions and a gram-scale reaction could be realized without the loss of the yield and enantioselectivity.