Atroposelective Synthesis of Planar-Chiral Indoles via Carbene Catalyzed Macrocyclization.

Indole-based planar-chiral macrocycles are widely found in natural products and bioactive molecules. However, in sharp contrast to the preparation of indole-based axially chiral structures, the enantioselective catalysis of indole-based planar-chiral macrocycles is still a formidable task so far. Here we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular atroposelective macrocyclization of 3-carboxaldehyde indole/pyrroles, featuring with broad substrate scope and good functional group tolerance, and allowing for a rapid access to diverse indole/pyrrole-based planar-chiral macrocycles with various tether-lengths (10-16 members) in good yields and with excellent enantioselectivities. Importantly, the indole-based macrocyclic structures with both planar and axial chirality were directly and efficiently obtained through this protocol with excellent enantioselectivities and diastereoselectivities. In addition, these synthesized planar-chiral macrocycles offer many possibilities for chemists to develop new catalysts or ligands, as well as new reactions.

Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Organocatalytic Higher-Order [8+2] Cycloaddition for the Assembly of Atropoenantiomeric 3-Arylindolizines.

We present an unprecedented atroposelective [8+2] cycloaddition reaction between pyridinium/isoquinolinium ylides and ynals. It is worth noting that this protocol represents a new example of the organocatalyzed atropoenantioselective higher-order cycloaddition reaction, providing various axial chiral 3-arylindolizines in good yields and high enantioselectivities. In addition, the obtained axially chiral 3-aryldolizines also provide many opportunities for structural transformations and potential drug discovery.

Organocatalytic atroposelective heterocycloaddition to access axially chiral 2-arylquinolines.

Axially chiral heterobiaryls play a vital role in asymmetric synthesis and drug discovery. However, there are few reports on the synthesis of atropisomeric heterobiaryls compared with axially chiral biaryls. Thus, the rapid enantioselective construction of optically active heterobiaryls and their analogues remains an attractive challenge. Here, we report a concise chiral amine-catalyzed atroposelective heterocycloaddition reaction of alkynes with ortho-aminoarylaldehydes, and obtain a new class of axially chiral 2-arylquinoline skeletons with high yields and excellent enantioselectivities. In addition, the axially chiral 2-arylquinoline framework with different substituents is expected to be widely used in enantioselective synthesis.

NHC-catalyzed atropoenantioselective synthesis of axially chiral biaryl amino alcohols via a cooperative strategy.

Axially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. However, only a very few enantioselective methods have been reported to synthesize chiral biaryl amino-alcohols. Therefore, the rapid enantioselective construction of optically active biaryl amino-alcohols still remains a formidable challenge. Here we report an N-heterocyclic carbene (NHC)-catalyzed atropoenantioselective acylation of biphenols triggered by a cooperative strategy consisting of desymmetrization followed by kinetic resolution. This protocol features broad substrate scope and good functional group tolerance, and allows for a rapid construction of axially chiral biaryl amino-alcohols in good to high yields and with excellent enantioselectivities. Furthermore, the structurally diverse axially chiral biaryl amino-alcohol derivatives provide multiple possibilities for chemists to develop catalysts or ligands for different chemical transformations.

Preparation and Characterization of Antioxidant Peptides from Fermented Goat Placenta.

The goat placenta was fermented by Bacillus subtilis and the optimal fermentation parameters of strongest antioxidant capacity of peptides were obtained using response surface methodology (RSM). The effects of fermentation time, initial pH value and glucose content on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity of the goat peptides were well fitted to a quadric equation with high determination coefficients. According to the data analysis of design expert, the strongest DPPH radical scavenging capacity value was obtained with the following conditions: content of glucose was 2.23%, initial pH value was 7.00 and fermentation time was 32.15 h. The DPPH radical scavenging capacity commonly referring antioxidant activity showed a concentration dependency and increased with increasing peptide concentration. The effects of temperature and pH were assessed to determine the stability of antioxidant peptides prepared from goat placenta. Antioxidant peptides showed good stabilities when temperature was lower than 70℃. However, the antioxidant peptides lost antioxidant activities rapidly under alkaline and excessive acid condition. Ultrafiltration technique was performed to separate fermentation broth with different Mw (molecular weight). It was found that peptides in the range of < 3 KDa mainly accounted for the antioxidant activities.

Inhibition of HBV replication by theophylline.

We have suggested recently that ATM-Rad3-Related (ATR) DNA damage signaling pathway, which responds to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells showed decreased HBV DNA yields, implying HBV infection and replication activate and exploit the activated DNA damage response. Host cell proteins may constitute an attractive target for anti-HBV-1 therapeutics, since development of drug resistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that one of the clinically used compounds of ATR and ataxia telangiectasia-mutated (ATM) kinases inhibitor, theophylline (Tp), significantly reduced the yield of HBV DNA, HBsAg and HBeAg in HepG2215 cell culture system, furthermore, Tp could also suppress serum HBV DNA and HBsAg levels in the HBV-transgenic mice. Consistent with this result, immunohistology also showed reduced intensity of HBsAg staining on livers from Tp-treatment group. Taken together, these data indicated the feasibility of therapeutic approaches that target host cell proteins by inhibiting a cellular gene that was required for HBV replication and provided a potential approach for the prevention and treatment of HBV infection.