Site- and Enantioselective Manganese-Catalyzed Benzylic C-H Azidation of Indolines.

A manganese-catalyzed highly site- and enantioselective benzylic C-H azidation of indolines has been described. The practical method is applicable for azidation of a tertiary benzylic C-H bond with good functional group tolerance, allowing facile access to structurally diverse tertiary azide-containing indolines in high efficiency with excellent site-, chemo-, and enantioselectivity. The generality of the method was further demonstrated by site- and enantioselective azidation of the secondary benzylic C-H bond for a range of secondary azide-containing indolines. The benzylic C-H azidation method allows to straightforwardly and enantioselectively install a variety of nitrogen-based functional groups and diverse bioactive molecules at the C3 position of indoline frameworks through post-azidation manipulations. Gram-scale synthesis was also demonstrated, further highlighting the synthetic potential of the method. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity.

Design, synthesis and biological evaluation of novel 1,3,4,9-tetrahydropyrano[3,4-b]indoles as potential treatment of triple negative breast cancer by suppressing PI3K/AKT/mTOR pathway.

Triple-negative breast cancer (TNBC) represents a subset of breast cancer characterized by high aggressiveness and poor prognosis. Currently, there is no curative therapeutic regimen for TNBC patients. In this study, molecular hybridization strategy is adopted by combining benzopyran and indole pharmacophores together, and a library of structurally simple 1,3,4,9-tetrahydropyrano[3,4-b]indoles was rapidly constructed. The structure-activity relationship studies indicated that compound 23 exhibited the most potent effect against the MDA-MB-231 cells with IC50 value of 2.29 µM. Mechanistic studies revealed that compound 23 inhibited cell proliferation via arresting cell cycle at G0/G1 phase. It induced cell apoptosis by disruption of mitochondrial membrane potential (MMP), accumulation of reactive oxygen species (ROS), reduction of glutathione (GSH), elevation of intracellular calcium ion (Ca2+) and activation of caspase cascade. Furthermore, compound 23 significantly inhibited the regulators of PI3K/AKT/mTOR pathway in MDA-MB-231 cells, suggesting that PI3K/AKT/mTOR pathway was involved in the 23-mediated apoptosis. To our knowledge, this is the first example of the anti-cancer activity study of indole-fused pyrans through suppressing PI3K/AKT/mTOR pathway. Overall, the current study suggested that compound 23 would serve as a promising lead compound for TNBC treatment.

Oxidative Kinetic Resolution of Cyclic Benzylic Ethers.

A manganese-catalyzed oxidative kinetic resolution of cyclic benzylic ethers through asymmetric C(sp3 )-H oxidation is reported. The practical approach is applicable to a wide range of 1,3-dihydroisobenzofurans bearing diverse functional groups and substituent patterns at the α position with extremely efficient enantiodiscrimination. The generality of the strategy was further demonstrated by efficient oxidative kinetic resolution of another type of five-membered cyclic benzylic ether, 2,3-dihydrobenzofurans, and six-membered 6H-benzo[c]chromenes. Direct late-stage oxidative kinetic resolution of bioactive molecules that are otherwise difficult to access was further explored.

A novel series of 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing 1,2,3-triazole group: Design, synthesis and antibacterial evaluation.

A series of novel 11-O-carbamoyl-3-O-descladinosyl clarithromycin derivatives bearing the 1,2,3-triazole group were designed, synthesized, and evaluated for their in vitro antibacterial activity. The antibacterial results indicated that most of the target compounds not only increased their activity against resistant bacterial strains, but also partially retained the activity against sensitive bacterial strains compared with clarithromycin. Among them, 13d had the best antibacterial activity against resistant strains, including Streptococcus pneumoniae B1 expressing the ermB gene (16 µg/mL), Streptococcus pneumoniae AB11 expressing the mefA and ermB genes (16 µg/mL) and Streptococcus pyogenes R1 (16 µg/mL), showing >16, 8 and 16-fold higher activity than that of CAM, respectively. Moreover, 13d and 13g exhibited the best antibacterial activity against sensitive bacterial strains, including Staphylococcus aureus ATCC25923 (4 µg/mL) and Bacillus Subtilis ATCC9372 (1 µg/mL). The MBC results showed that the most promising compounds 13d and 13g exhibited antibacterial activity through bacteriostatic mechanism, while the time-kill kinetic experiment revealed bactericidal kinetics of 13g from microscopic point of view. In vitro antibacterial experiments and molecular docking results further confirmed that it was feasible to our initial design strategy by modifying the C-3 and C-11 positions of clarithromycin to increase the activity against resistant bacteria.

Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors.

Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.