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. First, a reinforcement learning model is constructed for T2DM risk factors. Second, the process involved in the causal discovery method for T2DM risk factors is detailed. Finally, several experiments are designed based on diabetes datasets and used to verify the proposed approach. CONCLUSIONS: The experimental results show that the proposed approach improves the accuracy of causality mining between T2DM risk factors and provides new evidence to researchers engaged in T2DM prevention and treatment research.

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 10.1002/chem.202300960.

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. Additionally, by using the newly developed strategy, 9 aa, which exhibited excellent anticancer activity, can be prepared by a sequential transformation. In particularly, 9 aa suppressed HeLa cells with IC50 values of 74.5 nM, thus providing a promising lead compound for future drug discovery.

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 (H5L) with rich metal-chelating sites to construct an unusual and discrete 3d-4f metallacage, [Zn2Er4(H2L)4(NO3)Cl2(H2O)]·NO3·xCH3OH·yH2O (Zn2Er4). The 3d-4f Zn2Er4 cage possesses a quadruple-stranded structure, and all of the ligands wrap around an open spherical cavity within the core. The self-assembly of the unique cage not only ensures the structural stability of the Zn2Er4 cage as a nanoreactor in solution but also makes the bimetallic lanthanide cluster units active sites that are exposed in the medium-sized cavity. It is important to note that the Zn2Er4 cage as a homogeneous catalyst has been successfully applied to catalyze three-component aza-Darzens reactions of formaldehyde, anilines, and α-diazo esters without another additive under mild conditions, displaying better catalytic activity, higher specificity, short reaction time, and low catalyst loadings. A possible mechanism for this three-component aza-Darzens reaction catalyzed by the Zn2Er4 cage has been proposed. These experimental results have demonstrated the great potential of the discrete 3d-4f metallacage as a host nanoreactor for the development of supramolecular or molecular catalysis.

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

(S)-2-Hydroxypropylphosphonate [(S)-2-HPP, 1] epoxidase (HppE) reduces H2O2 at its nonheme-iron cofactor to install the oxirane "warhead" of the antibiotic fosfomycin. The net replacement of the C1 pro-R hydrogen of 1 by its C2 oxygen, with inversion of configuration at C1, yields the cis-epoxide of the drug [(1R,2S)-epoxypropylphosphonic acid (cis-Fos, 2)]. Here we show that HppE achieves ∼95% selectivity for C1 inversion and cis-epoxide formation via steric guidance of a radical-coupling mechanism. Published structures of the HppE·FeII·1 and HppE·ZnII·2 complexes reveal distinct pockets for C3 of the substrate and product and identify four hydrophobic residues-Leu120, Leu144, Phe182, and Leu193-close to C3 in one of the complexes. Replacement of Leu193 in the substrate C3 pocket with the bulkier Phe enhances stereoselectivity (cis:trans ∼99:1), whereas the Leu120Phe substitution in the product C3 pocket diminishes it (∼82:18). Retention of C1 configuration and trans-epoxide formation become predominant with the bulk-reducing Phe182Ala substitution in the substrate C3 pocket (∼13:87), trifluorination of C3 (∼23:77), or both (∼1:99). The effect of C3 trifluorination is counteracted by the more constrained substrate C3 pockets in the Leu193Phe (∼56:44) and Leu144Phe/Leu193Phe (∼90:10) variants. The ability of HppE to epoxidize substrate analogues bearing halogens at C3, C1, or both is inconsistent with a published hypothesis of polar cyclization via a C1 carbocation. Rather, specific enzyme-substrate contacts drive inversion of the C1 radical-as proposed in a recent computational study-to direct formation of the more potently antibacterial cis-epoxide by radicaloid C-O coupling.

Recyclable and Stable α-Methylproline-Derived Chiral Ligands for the Chemical Dynamic Kinetic Resolution of free C,N-Unprotected α-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. Herein, we describe a detailed biochemical investigation of a Fom3 that is purified with 1 equiv of its cobalamin cofactor bound, which is almost exclusively in the form of MeCbl. Electron paramagnetic resonance and Mössbauer spectroscopies confirm that Fom3 contains one [4Fe-4S] cluster. Using deuterated enantiomers of HEP-CMP, we demonstrate that the 5'-dA• generated by Fom3 abstracts the C2″- pro-R hydrogen of HEP-CMP and that methyl addition takes place with inversion of configuration to yield solely ( S)-HPP-CMP. Fom3 also sluggishly converts cytidylyl-ethylphosphonate to the corresponding methylated product but more readily acts on cytidylyl-2-fluoroethylphosphonate, which exhibits a lower C2″ homolytic bond-dissociation energy. Our studies suggest a mechanism in which the substrate C2″ radical, generated upon hydrogen atom abstraction by the 5'-dA•, directly attacks MeCbl to transfer a methyl radical (CH3•) rather than a methyl cation (CH3+), directly forming cob(II)alamin in the process.

Chemical Resolution of C, N-Unprotected α-Substituted ß-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 ß-amino acids (ß2-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic ß2-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 ß2-AAs could be obtained by simple hydrolysis of an isolated favored Ni(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of ß2-AAs.

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 (<57.6% at 5 µM) compared with berberine on gluconeogenesis in rat primary hepatocytes. Additionally, these compounds significantly up-regulated the phosphorylation of AMPK and its substrate, acetyl-CoA carboxylase (ACC) and slightly decreased the mitochondrial membrane potential in L6 myotube cells.

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. These attractive characteristics, combined with simplicity of reaction conditions and virtually complete stereochemical outcome, constitute a true methodological advance in this area, rivaling previously reported chemical and biocatalytic approaches.

[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. The strategies for lead compound optimization are to reduce inhibitory activity of hERG potassium channel and decrease cardiac toxicity. These methods include reduction of lipophilicity and basicity of amines, introduction of hydroxyl and acidic groups, and restricting conformation.

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.

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.

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.

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 chiral heterocyclic amino acids via the alkylation of the Ni(II) complex of glycine and alkyl halides.

An investigation into the reactivity profile of alkyl halides has led to the development of a new method for the asymmetric synthesis of chiral heterocyclic amino acids. This protocol involves the asymmetric alkylation of the Ni(II) complex of glycine to form an intermediate, which then decomposes to form a series of valuable chiral amino acids in high yields and with excellent diastereoselectivity. The chiral amino acids underwent a smooth intramolecular cyclization process to afford the valuable chiral heterocyclic amino acids in high yields and enantioselectivities. This result paves the way for the development of a new synthetic method for chiral heterocyclic amino acids.

Design, synthesis and evaluation of benzo[a]thieno[3,2-g]quinolizines as novel l-SPD derivatives possessing dopamine D1, D2 and serotonin 5-HT1A multiple action profiles.

A novel scaffold derived from l-SPD with a substituted thiophene group in the D ring were designed, synthesized, and evaluated for their binding affinities at dopamine (D1, D2 and D3) and serotonin (5-HT1A and 5-HT2A) receptors. Most of the tetracyclic compounds exhibited higher affinities for D2 and 5-HT1A receptors than l-SPD, while compound 23 e showed the highest Ki value of 7.54 nM at D2 receptor which was 14 times more potent than l-SPD. Additionally, compounds 23 d and 23 e were more potent than l-SPD at D3 receptor. According to the functional assays, 23 d and 23 e were demonstrated as full antagonists at D1 and D2 receptors and full agonists at 5-HT1A receptor. Since the combination of D2 antagonism and 5-HT1A agonism is considered effective in treating both the positive and negative symptoms of schizophrenia, these novel compounds are implicated as potential therapeutic agents.

Chemical kinetic resolution of unprotected ß-substituted ß-amino acids using recyclable chiral ligands.

The first chemical method for resolution of N,C-unprotected ß-amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target ß-substituted-ß-amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including ß-aryl, ß-heteroaryl, and ß-alkyl-derived ß-amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti-diabetic drug sitagliptin.

Electrochemical oxidative cyclization of N-allylamides for the synthesis of CF3-containing benzoxazines and oxazolines.

The introduction of trifluoromethyl (-CF3) 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 N-(2-vinylphenyl)amides for the synthesis of CF3-containing benzoxazines and oxazolines was obtained. This sustainable protocol features inexpensive and durable electrodes, a wide range of substrates, diverse functional group compatibility under transition-metal-free, external-oxidant-free, and additive-free conditions, and can be applied in an open environment.

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. This model utilizes chemical reaction templates and commercially available building blocks as a starting point and employs forward reaction prediction to generate molecules, while real-time docking and drug-likeness predictions are conducted to ensure synthesizability and drug-likeness. We applied this model to design active molecules targeting the inflammation-related receptor CXCR4 and successfully prepared them according to the AI-proposed synthetic routes. Several molecules exhibited potent anti-CXCR4 and anti-inflammatory activity in subsequent in vitro and in vivo assays. The top-performing compound XVI alleviated symptoms related to inflammatory bowel disease and showed reasonable pharmacokinetic properties.