Synthetically Feasible De Novo Molecular Design of Leads Based on a Reinforcement Learning Model: AI-Assisted Discovery of an Anti-IBD Lead Targeting CXCR4.

Artificial intelligence (AI) de novo molecular generation provides leads with novel structures for drug discovery. However, the target affinity and synthesizability of the generated molecules present critical challenges for the successful application of AI technology. Therefore, we developed an advanced reinforcement learning model to bridge the gap between the theory of de novo molecular generation and the practical aspects of drug discovery.

Electrochemical oxidative cyclization of -allylamides for the synthesis of CF-containing benzoxazines and oxazolines.

The introduction of trifluoromethyl (-CF) groups into compounds is a common synthetic strategy in organic chemistry. Commonly used methods for introducing trifluoromethyl groups are limited by harsh reaction conditions, low regioselectivity, or the need for excess reagents. In this study, a facile electrochemical oxidative and radical cascade cyclization of -(2-vinylphenyl)amides for the synthesis of CF-containing benzoxazines and oxazolines was obtained.

Causal discovery approach with reinforcement learning for risk factors of type II diabetes mellitus.

Background: Statistical correlation analysis is currently the most typically used approach for investigating the risk factors of type 2 diabetes mellitus (T2DM). However, this approach does not readily reveal the causal relationships between risk factors and rarely describes the causal relationships visually.

Results: Considering the superiority of reinforcement learning in prediction, a causal discovery approach with reinforcement learning for T2DM risk factors is proposed herein.

Late-Stage Functionalization for the Divergent Synthesis of Podophyllotoxin Derivatives by Rhodium Catalysis.

Invited for the cover of this issue are Chunpu Li, Hong Liu and co-workers at Shanghai Institute of Materia Medica, Nanjing University of Chinese Medicine, and Hangzhou Institute for Advanced Study. The image depicts rhodium catalysis converting the readily available podophyllotoxin into four kinds of novel derivatives. Read the full text of the article at 10.

Mesoporous Mixed-Metal-Organic Framework Incorporating a [Ru(Phen)] Photosensitizer for Highly Efficient Aerobic Photocatalytic Oxidative Coupling of Amines.

[Ru(Phen)] (phen = phenanthroline) as a very classical photosensitizer possesses strong absorption in the visible range and facilitates photoinduced electron transfer, which plays a vital role in regulating photochemical reactions. However, it remains a significant challenge to utilize more adequately and exploit more efficiently the ruthenium-based materials due to the uniqueness, scarcity, and nonrenewal of the noble metal. Here, we integrate the intrinsic advantages of the ruthenium-based photosensitizer and mesoporous metal-organic frameworks (meso-MOFs) into a [Ru(Phen)] photosensitizer-embedded heterometallic Ni(II)/Ru(II) meso-MOF () via the metalloligand approach.

Rh(III)-Catalyzed Synthesis of Substituted Isoindoles through a Direct C-H Activation/[4 + 1] Annulation and Acyl Migration Cascade of Oxadiazolones with Diazo Compounds.

A Rh(III)-catalyzed C-H bond activation for the synthesis of fused 2-isoindole scaffolds from oxadiazolones with diazo compounds was developed. The reaction proceeded through C-H activation of oxadiazolones/[4 + 1] annulation, intramolecular cyclization, and an unusual acyl migration cascade to afford target scaffolds with good yields. These 2-isoindole derivatives could be further transformed into intriguing drug privileged scaffolds.

Late-Stage Functionalization for the Divergent Synthesis of Podophyllotoxin Derivatives by Rhodium Catalysis.

A divergent synthesis of podophyllotoxin derivatives from simple and readily available starting materials through a late-stage functionalization strategy by rhodium catalysis is reported here. This strategy uses the ketone and oxime in substrates as directing groups. Four kinds of novel podophyllotoxin derivatives have been obtained without any erosion of the enantiopurity, thus indicating the broad substrate scope of this method.

A Discrete 3d-4f Metallacage as an Efficient Catalytic Nanoreactor for a Three-Component Aza-Darzens Reaction.

The exploration and development of coordination nanocages can provide an approach to control chemical reactions beyond the bounds of the flask, which has aroused great interest due to their significant applications in the field of molecular recognition, supramolecular catalysis, and molecular self-assembly. Herein, we take the advantage of a semirigid and nonsymmetric bridging ligand (H) with rich metal-chelating sites to construct an unusual and discrete 3d-4f metallacage, [ZnEr(H)(NO)Cl(HO)]·NO·CHOH·HO (). The 3d-4f cage possesses a quadruple-stranded structure, and all of the ligands wrap around an open spherical cavity within the core.

Hybrid radical-polar pathway for excision of ethylene from 2-oxoglutarate by an iron oxygenase.

Microbial ethylene-forming enzyme (EFE) converts the C3–C4 fragment of the ubiquitous primary metabolite 2-oxoglutarate (2OG) to its namesake alkene product. This reaction is very different from the simple decarboxylation of 2OG to succinate promoted by related enzymes and has inspired disparate mechanistic hypotheses. We show that EFE produces stereochemically random (equal cis and trans) 1,2-[H]-ethylene from (3,4)-[H]-2OG, appends an oxygen from O on the C1-derived (bi)carbonate, and can be diverted to ω-hydroxylated monoacid products by modifications to 2OG or the enzyme.

Improved Functional Causal Likelihood-Based Causal Discovery Method for Diabetes Risk Factors.

Diabetes mellitus is a disease that has reached epidemic proportions globally in recent years. Consequently, the prevention and treatment of diabetes have become key social challenges. Most of the research on diabetes risk factors has focused on correlation analysis with little investigation into the causality of these risk factors.

Steric Enforcement of -Epoxide Formation in the Radical C-O-Coupling Reaction by Which ()-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin.

()-2-Hydroxypropylphosphonate [()-2-HPP, ] epoxidase (HppE) reduces HO at its nonheme-iron cofactor to install the oxirane "warhead" of the antibiotic fosfomycin. The net replacement of the C1 hydrogen of by its C2 oxygen, with inversion of configuration at C1, yields the -epoxide of the drug [(1,2)-epoxypropylphosphonic acid (-Fos, )]. Here we show that HppE achieves ∼95% selectivity for C1 inversion and -epoxide formation via steric guidance of a radical-coupling mechanism.

Recyclable and Stable -Methylproline-Derived Chiral Ligands for the Chemical Dynamic Kinetic Resolution of free -Unprotected -Amino Acids.

A novel special designed, stable, and recyclable chiral ligand bearing a quaternary carbon was developed for chemical dynamic kinetic resolution (DKR) of free C,N-unprotected racemic α-amino acids via Schiff base intermediates. This method furnishes high yields with excellent enantioselectivity, has a broad substrate scope, and uses operationally simple and convenient conditions. The present chemical DKR is a practical and useful method for the preparation of enantiopure α-amino acids.

Stereochemical and Mechanistic Investigation of the Reaction Catalyzed by Fom3 from Streptomyces fradiae, a Cobalamin-Dependent Radical S-Adenosylmethionine Methylase.

Fom3, a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase, has recently been shown to catalyze the methylation of carbon 2″ of cytidylyl-2-hydroxyethylphosphonate (HEP-CMP) to form cytidylyl-2-hydroxypropylphosphonate (HPP-CMP) during the biosynthesis of fosfomycin, a broad-spectrum antibiotic. It has been hypothesized that a 5'-deoxyadenosyl 5'-radical (5'-dA) generated from the reductive cleavage of SAM abstracts a hydrogen atom from HEP-CMP to prime the substrate for addition of a methyl group from methylcobalamin (MeCbl); however, the mechanistic details of this reaction remain elusive. Moreover, it has been reported that Fom3 catalyzes the methylation of HEP-CMP to give a mixture of the ( S)-HPP and ( R)-HPP stereoisomers, which is rare for an enzyme-catalyzed reaction.

Chemical Resolution of C, N-Unprotected α-Substituted β-Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands.

We report the first purely chemical method for the resolution of C, N-unprotected racemic α-substituted β-amino acids (β-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β-AAs along with Ni(II) could form a pair of Ni(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure C, N-unprotected β-AAs could be obtained by simple hydrolysis of an isolated favored Ni(II) complex.

Design, synthesis, and structure-activity relationships of novel 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinoline and 5,8,12,12a-tetrahydro-6H-thieno[2',3':4,5]pyrido[2,1-a]isoquinoline derivatives as cellular activators of adenosine 5'-monophosphate-activated protein kinase (AMPK).

To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinoline or 5,8,12,12a-tetrahydro-6H-thieno[2',3':4,5]pyrido[2,1-a]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5'-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 μM) in L6 myotube cells, and two compounds (4d and 4s) exhibited superior inhibitory activity (<57.

Design, synthesis and biological evaluation of 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines as novel adenosine 5'-monophosphate-activated protein kinase (AMPK) indirect activators for the treatment of type 2 diabetes.

A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.

[Lead compound optimization strategy(5) – reducing the hERG cardiac toxicity in drug development].

The potassium channel encoded by the human ether-a-go-go related gene(hERG) plays a very important role in the physiological and pathological processes in human. hERG potassium channel determines the outward currents which facilitate the repolarization of the myocardial cells. Some drugs were withdrawn from the market for the serious side effect of long QT interval and arrhythmia due to blockade of hERG channel.

Purely Chemical Approach for Preparation of d-α-Amino Acids via (S)-to-(R)-Interconversion of Unprotected Tailor-Made α-Amino Acids.

Unnatural (R)-α-amino acids (α-AAs) are in growing demand in the biomedical research and pharmaceutical industries. In this work, we present development of a purely chemical approach for preparation of (R)-α-AAs via (S)-to-(R)-interconversion of natural and tailor-made (S)-α-AAs. The method can be used on free, unprotected α-AAs and features a remarkable structural generality including substrates bearing tertiary alkyl chains and reactive functional groups.

The facile construction of the phthalazin-1(2H)-one scaffold via copper-mediated C-H(sp(2))/C-H(sp) coupling under mild conditions.

A novel strategy for the construction of the phthalazin-1(2H)-one scaffold has been developed by means of a copper-mediated cascade C-H/C-H coupling and intramolecular annulations and a subsequent facile hydrazinolysis. This C-H activation transformation proceeds smoothly with wide generality, good functional tolerance and high stereo- and regioselectivity under mild conditions. Through the removal of the directing group, the resulting moiety could easily be transformed into the phthalazin-1(2H)-one scaffold, which is known to be a privileged moiety and a bioactive nucleus in pharmaceuticals.

Asymmetric Synthesis of (2S,3S)-α-(1-Oxoisoindolin-3-yl)glycines under Low-Basicity "Kinetic" Control.

The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.

Recyclable Ligands for the Non-Enzymatic Dynamic Kinetic Resolution of Challenging α-Amino Acids.

Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor-made α-amino acids (TM-α-AAs), enabling the first DKR of TM-α-AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM-α-AAs, especially on large scale.

Chemical Dynamic Thermodynamic Resolution and S/R Interconversion of Unprotected Unnatural Tailor-made α-Amino Acids.

Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and S/R interconversion of unprotected tailor-made α-amino acids (α-AAs) through intermediate formation of the corresponding nickel(II)-chelated Schiff bases. The method features virtually complete stereochemical outcome, broad substrate generality (35 examples), and operationally convenient conditions allowing for large-scale preparation of the target α-AAs in enantiomerically pure form. Furthermore, the new type of nonracemizable axially chiral ligands can be quantitatively recycled and reused, rendering the whole process economically and synthetically attractive.

Site-specific indolation of proline-based peptides via copper(II)-catalyzed oxidative coupling of tertiary amine N-oxides.

The first site-specific and purely chemical method for modifying proline-based peptides was developed via a convenient, copper-catalyzed oxidative coupling of tertiary amine N-oxides with indoles. This novel approach features high regioselectivity and diastereoselectivity, mild conditions, and compatibility with various functional groups. In addition, a simplified process was realized in one pot and two steps via in situ oxidative coupling of tertiary amine and indoles.

Asymmetric synthesis of α-(1-oxoisoindolin-3-yl)glycine: synthetic and mechanistic challenges.

We report herein that the NaOMe-catalyzed reactions between the chiral glycine Schiff base (S)-4 with 2-cyanobenzaldehyde 3a provide for a convenient preparation of the novel α-(1-oxoisoindolin-3-yl)glycine 1 of high pharmaceutical potential. The reactions involve at least eight synthetic steps and can mechanistically be realized only with application of Ni(II) complexes described in this study.