Aryl boronic acid-controlled divergent ring-contraction and ring-opening/isomerization reaction of tert-cyclobutanols enabled by nickel catalysis.

In this work, we wish to present a nickel-catalyzed divergent ring-contraction and ring-opening/isomerization reaction of tert-cyclobutanols. The key to control these two different reaction pathways is to choose appropriate boronic acid, where the use of phenylboronic acid and pyrimidin-5-ylboronic acid enables a ring-contraction and ring-opening reaction/isomerization, respectively. Both cyclopropyl aryl methanones and 1-aryl butan-1-ones could be selectively obtained.

Nickel-catalyzed divergent formylation and carboxylation of aryl halides with isocyanides.

Herein, we describe a nickel-catalyzed divergent formylation and carboxylation reaction of aryl halides with isocyanides. A rich array of aromatic aldehydes and carboxylic acids can be, respectively, accessed in moderate to good yields. Some sensitive functional groups such as hydroxyl, iodine, cyano, and indolyl are fairly tolerant of nickel catalysis. In the carboxylation reactions, the combination of isocyanide and H2O is first employed as a promising carbonyl surrogate instead of gaseous CO and CO2.

A combination of the modified catalytic core and conjugation of 3'-inverted deoxythymidine for a more efficient and nuclease-resistant 10-23 DNAzyme.

10-23 DNAzyme is a catalytic DNA molecule capable of cleaving complementary RNA. Its high cleavage efficiency is being pursued by chemical modifications, for realizing its genetic therapeutics potential. The most efficient and nuclease-resistant DNAzyme was obtained in this study combined two modifications - 7-aminopropyl-8-aza-7-deaza-2'-deoxyadenosine (residue 1) at A9 and 3'-inverted deoxythymidine residue (iT) at 3'-end. Moreover, this combinatorial modification could be a universal approach for designing efficient and enzyme-resistant 10-23 DNAzyme against other RNA targets, and the catalytic core-modification could be further combined with other recognition arm modifications for practical applications as genetic therapeutics and biosensor tools.

Nickel-catalyzed cascade hydrosilylation/cyclization of 1,7-enynes leading to silyl-containing quinolinones.

We herein describe a nickel-catalyzed cascade hydrosilylation/cyclization reaction of 1,7-enynes with bulky triphenylsilane. A series of silyl-containing quinolinone derivatives are obtained in good to excellent yields under mild reaction conditions. This reaction also features excellent chemoselectivity, broad functional group tolerance, and gram-scale synthesis.

Nickel-catalyzed cyanation reaction of aryl/alkenyl halides with alkyl isocyanides.

We herein describe a nickel-catalyzed cyanation reaction of aryl/alkenyl halides with alkyl isocyanides. Both aryl/alkenyl iodines and bromides were found to be competent electrophiles that reacted with alkyl isocyanides, affording nitrile compounds in moderate to good yields. A range of functional groups including halogens as well as hydroxyl, formyl, and acetamino groups were fairly compatible with the nickel catalysis. This protocol featured broad functional group tolerance, simple reaction conditions, and gram-scale synthesis.

Concise Biosynthesis of Tropone-Containing Spiromaterpenes by a Sesquiterpene Cyclase and a Multifunctional P450 from a Deep-Sea-Derived Spiromastix sp. Fungus.

Spiromaterpenes are a group of rare tropone-containing sesquiterpenes with antineuroinflammatory activity. Herein, we elucidate their biosynthetic pathway in a deep-sea-derived Spiromastix sp. fungus by heterologous expression, biochemical characterization, and incubation experiments. The sesquiterpene cyclase SptA was first characterized to catalyze the production of guaia-1(5),6-diene, and a multifunctional cytochrome P450 catalyzed the tropone ring formation. These results provide important clues for the rational mining of bioactive guaiane-type sesquiterpenes and expand the repertoire of P450 activities to synthesize unique building blocks of natural products.

Nickel-Catalyzed Arylation/Alkenylation of tert-Cyclobutanols with Aryl/Alkenyl Triflates via a C-C Bond Cleavage.

Herein, we first present a nickel-catalyzed arylation and alkenylation of tert-cyclobutanols with aryl/alkenyl triflates via a C-C bond cleavage. An array of γ-substituted ketones was obtained in moderate-to-good yields, thus featuring earth-abundant nickel catalysis, broad substrate scope, and simple reaction conditions. Preliminary mechanistic experiments indicated that ß-carbon elimination pathways might be involved in the catalytic cycle.

Nickel-catalyzed remote hydrosilylation of unconjugated enones with bulky triphenylsilane.

Herein we describe a nickel-catalyzed remote hydrosilylation of unconjugated enones with bulky triphenylsilane. A range of Z-silyl enol ethers are obtained as major isomers due to the process of nickel triggered alkene isomerization. Notably, some specific alkyl silyl enol ethers can be prepared from this protocol, which are not easily accessed by the traditional strategy using a strong base and chlorosilane. This reaction features 100% atom economy, simple reaction conditions, and good yields.

NHC-catalyzed Truce-Smiles rearrangement of N-aryl methacrylamides for the synthesis of trans-cinnamides.

Herein we describe a NHC-catalyzed Truce-Smiles rearrangement of N-aryl methacrylamides which enables the cleavage of an inert aryl C-N bond. A range of trans-cinnamides could be obtained by the direct construction of a C(aryl)-C(alkenyl) bond and functional groups such as Br, Cl, CN, and pyridinyl are compatible with NHC catalysis. The reaction features high atom-economy, transition-metal free catalysis, and easily available substrates.

Chemical Space, Scaffolds, and Halogenated Compounds of CMNPD: A Comprehensive Chemoinformatic Analysis.

The comprehensive marine natural products database (CMNPD) is a new free access and comprehensive database developed originally by Lyu's team of our research group, including more than 30 000 marine natural products (MNPs) reported from the 1960s. In this article, we aimed to present CMNPD's value in drug discovery and to present several characteristics of MNPs based on our new comprehensive data. We used chemoinformatic analysis methods to report the molecular properties, chemical space, and several scaffold assessments of CMNPD compared with several databases. Then, we reported the characteristics of MNPs from the aspect of halogens, comparing MNPs with terrestrial natural products (TNPs) and drugs. We found that CMNPD had a low proportion (2.91%) of scaffolds utilized by drugs, and high similarities between CMNPD and NPAtlas (a microbial natural products database), which are worth further investigation. The proportion of bromides in MNPs is outstandingly higher (11.0%) in contrast to other halogens. Furthermore, the results showed great differences in halogenated structures between MNPs and drugs, especially brominated substructures. Finally, we found that many marine species (2.52%) reported only halogenated compounds. It can be concluded from these results that CMNPD is a promising source for drug discovery and has many scientific issues relative to MNPs that need to be further investigated.

Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation.

S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.

Integrated metabolomics and transcriptomics reveal di(2-ethylhexyl) phthalate-induced mitochondrial dysfunction and glucose metabolism disorder through oxidative stress in rat liver.

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous pollutant that results in hepatotoxicity. However, an understanding of the systematic mechanism of hepatic injury caused by DEHP remains limited. Here, we performed a comprehensive metabolomics and transcriptomics analyses to describe hepatic responses of rats to long-term DEHP exposure and, together with pathology and functional injury of liver, systematically analyzed the pathogenesis and mechanisms of liver damage. SD rats were exposed to 0 and 600 mg/kg/day DEHP for 12 weeks. Thereafter, biochemical indicators and histopathological changes regarding liver function were detected. Metabolomics and transcriptomics profiles of rat liver samples were analyzed using a UPLC-MS/MS system and Illumina Hiseq 4000, respectively. DEHP induced hepatocyte structural alterations and edema, depressed monooxygenase activity, decreased antioxidant activities, aggravated oxidative damage, blocked the tricarboxylic acid cycle and respiratory chain, and disturbed glucose homeostasis in the liver. These findings indicate that reactive oxygen species play a major role in these events. Overall, this study systematically depicts the comprehensive mechanisms of long-term DEHP exposure to liver injury and highlights the power of metabolomics and transcriptomics platforms in the mechanistic understanding of xenobiotic hepatotoxicity.

Target Prediction Model for Natural Products Using Transfer Learning.

A large proportion of lead compounds are derived from natural products. However, most natural products have not been fully tested for their targets. To help resolve this problem, a model using transfer learning was built to predict targets for natural products. The model was pre-trained on a processed ChEMBL dataset and then fine-tuned on a natural product dataset. Benefitting from transfer learning and the data balancing technique, the model achieved a highly promising area under the receiver operating characteristic curve (AUROC) score of 0.910, with limited task-related training samples. Since the embedding distribution difference is reduced, embedding space analysis demonstrates that the model's outputs of natural products are reliable. Case studies have proved our model's performance in drug datasets. The fine-tuned model can successfully output all the targets of 62 drugs. Compared with a previous study, our model achieved better results in terms of both AUROC validation and its success rate for obtaining active targets among the top ones. The target prediction model using transfer learning can be applied in the field of natural product-based drug discovery and has the potential to find more lead compounds or to assist researchers in drug repurposing.

Bifunctional Phosphine Ligand-Enabled Gold(I)-Catalyzed O-Nucleophilic Addition of N-Hydroxybenzo[1,2,3]-triazin-4(3H)-ones to Alkynes Followed by [3,3]-Rearrangement: Simultaneous Formation of C-O and C-N Bonds.

We describe a gold (I)-catalyzed tandem O-nucleophilic addition/[3,3]-rearrangement reaction of N-hydroxybenzo[1,2,3]-triazin-4(3H)-ones with alkynes enabled by a biphenyl-2-yl phosphine ligand featuring a pendant amide moiety (L1). A variety of 1-(2-oxo-2-arylethyl)benzo [d][1,2,3]triazin-4(1H)-one derivatives were synthesized in good to excellent yields. The present protocol gives a rare example of simultaneous formation of C-O and C-N bonds in the gold(I)-catalyzed [3,3]-sigmatropic rearrangements.

TF3P: Three-Dimensional Force Fields Fingerprint Learned by Deep Capsular Network.

Molecular fingerprints are the workhorse in ligand-based drug discovery. In recent years, an increasing number of research papers reported fascinating results on using deep neural networks to learn 2D molecular representations as fingerprints. It is anticipated that the integration of deep learning would also contribute to the prosperity of 3D fingerprints. Here, we unprecedentedly introduce deep learning into 3D small molecule fingerprints, presenting a new one we termed as the three-dimensional force fields fingerprint (TF3P). TF3P is learned by a deep capsular network whose training is in no need of labeled data sets for specific predictive tasks. TF3P can encode the 3D force fields information of molecules and demonstrates the stronger ability to capture 3D structural changes, to recognize molecules alike in 3D but not in 2D, and to identify similar targets inaccessible by other 2D or 3D fingerprints based on only ligands similarity. Furthermore, TF3P is compatible with both statistical models (e.g., similarity ensemble approach) and machine learning models. Altogether, we report TF3P as a new 3D small molecule fingerprint with a promising future in ligand-based drug discovery. All codes are written in Python and available at https://github.com/canisw/tf3p.

Discovery and antibacterial study of potential PPK1 inhibitors against uropathogenic E. coli.

Novel antibacterial agents are urgently needed to address the infections caused by multi-drug resistant bacteria. Urinary tract infections are common infectious diseases in clinical. Most of these infections are caused by drug-resistant uropathogenic Escherichia coli. PPK1 is an essential kinase for bacterial motility, biofilm formation, quorum sensing, and virulence factors in the expression of uropathogenic E. coli. In the present study, two small molecules potentially targeting PPK1 were discovered through virtual screening and biological assays. The in vitro and in vivo results suggested that the interaction of these compounds with PPK1 can disrupt biofilm formation of uropathogenic E. coli and reduce invasive ability and resistance to oxidative stress of this strain. Moreover, the compounds exhibit good antibacterial bacterial activity in the mice with urinary tract infection. Taken together, our findings could provide a new chemotype for the development of antibacterials targeting PPK1.

Revealing conformational dynamics of 2'-O-methyl-RNA guanine modified G-quadruplex by replica exchange molecular dynamics.

Thrombin-binding DNA aptamer (TBA) can fold into an antiparallel unimolecular G-quadruplex (G4) structure. Different types of modifications lead to various effects on the structure and stability of the G4 structure. Previous study has shown that a modified TBA (mTBA) that 2'-deoxy guanine (dG) at positions 10 and 11 in the TBA sequence were replaced by 2'-O-methyl-RNA guanine (2'OMe-G) can't fold into a well-defined G4 structure. In order to investigate the detailed structural information and probe the instability factors, we successfully employed the replica exchange molecular dynamics (REMD) to characterize the large conformational variations of the mTBA and systemically describe the influences of the 2'OMe-G on the mTBA in terms of conformation variations and the probability distributions of Hoogsteen hydrogen bonds, dihedral, sugar pucker and glycosyl torsion angle. Replacing position 10 with the 2'OMe-G (2'OMe-G10) induced a strong destabilization of the aptamer, while the 2'OMe-G at position 11(2'OMe-G11) was less destabilizing. More importantly, the glycosyl torsion angle and sugar pucker of 2'OMe-G10 were the most critical destabilization factors. These results were in good agreement with the theoretical and experimental results. Moreover, the structure information can be used as guidelines for the further design of modifications on G4 structure.

Structural and mechanistic insights into modified G-quadruplex thrombin-binding DNA aptamers.

Thrombin-binding aptamer (TBA) can fold into a G-quadruplex structure necessary for interacting with thrombin. When one thymidine residue of the TGT loop at position 7 is replaced with unlocked uracil (UNA), d-isothymidine (D-isoT) or l-isothymidine (L-isoT), these modified sequences display different activities. To date, the mechanisms of how D/L-isoT and UNA influence the biological properties of TBA have not been illustrated in the literature. In this paper, we fill this gap by probing the structure variations and binding modes of these modified TBAs via molecular dynamics (MD) simulation and free energy calculation. Comparative structural analyses demonstrated that both D-IsoT and UNA changed the local conformation of TGT loop and formed stronger interactions with the target protein. Particularly, D-IsoT and UNA adopted similar conformation which can well explain their similar biological activities. In addition, the flexibility of the two TT loops were described clearly. In contrast, L-IsoT at position 7 led to an obvious tendency to unfold. Free energy calculation and the analysis of key residues energy contributions eventually provide a clear picture of interactions for further understanding of the structure-activity relationships. Collectively, our findings open the way for a rational design of modified aptamers.

Rational Design and Identification of Small-Molecule Allosteric Inhibitors of CD38.

CD38 is a multi-functional signaling enzyme that catalyzes the biosynthesis of two calcium-mobilizing second messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. It also regulates intracellular nicotinamide adenine dinucleotide (NAD) contents, associated with multiple pathophysiological processes such as aging and cancer. As such, enzymatic inhibitors of CD38 offer great potential in drug development. Here, through virtual screening and enzymatic assays, we discovered compound LX-102, which targets CD38 on the side opposite its enzymatic pocket with a binding affinity of 7.7 µm. It inhibits the NADase activity of CD38 with an IC50 of 14.9 µm. Surface plasmon resonance (SPR) and hydrogen/deuterium exchange and mass spectrometry experiments verified that LX-102 competitively binds to the epitope of the therapeutic SAR 650984 antibody in an allosteric manner. Molecular dynamics simulation was performed to demonstrate the binding dynamics of CD38 with the allosteric ligand. In summary, we established that the cavity to which SAR 650984 binds was an allosteric site and was accessible for the rational design of small chemical modulators of CD38. The lead compound LX-102 that we identified in this study could also be a useful tool for probing CD38 functions and promoting drug discovery.

Diboron-Assisted Copper-Catalyzed Z-Selective Semihydrogenation of Alkynes Using Ethanol as a Hydrogen Donor.

We herein describe a B2Pin2-assisted copper-catalyzed semihydrogenation of alkynes. A variety of alkenes were obtained in good to excellent yields with Z-selectivity under mild reaction conditions. Mechanistic studies indicated that a transfer hydrogenation process was involved and ethanol acted as both a solvent and a hydrogen donor in this reaction. The present protocol enabled convenient synthesis of deuterium-substituted Z-alkenes such as Z-Combretastain A4- d2 in a high deuteration ratio by using readily available ethanol- d1 as the deuterium source.