Kinetically Controlled Stereoselective Synthesis of 2-Oxo-2-aryl-1,3,2-dioxaphosphorinane Derivatives via a Palladium-Catalyzed Reaction.

Chiral phosphonate esters have been widely applied in the fields of organic chemistry, medicine, and photoelectric materials. However, it requires the challenging enantioselective synthesis of cyclic phosphonate esters with the desired chiral configuration. The two epimers of 2-oxo-2H-1,3,2-dioxaphosphorinane derivatives should have different reactivities in Pd-catalyzed coupling reactions, which could lead to an effective methodology for the asymmetric synthesis of 2-oxo-2-aryl-1,3,2-dioxaphosphorinane derivatives. A thorough investigation of the coupling reactions both computationally and experimentally led to the stereoselective synthesis of chiral cyclic phosphonate esters. The axial isomer of products can be obtained with both high diastereoselectivity and good chemical yields from the mixture of 2-oxo-2H-1,3,2-dioxaphosphorinane derivatives under kinetically controlled conditions.

Bioinspired large Stokes shift small molecular dyes for biomedical fluorescence imaging.

Long Stokes shift dyes that minimize cross-talk between the excitation source and fluorescent emission to improve the signal-to-background ratio are highly desired for fluorescence imaging. However, simple small molecular dyes with large Stokes shift (more than 120 nanometers) and near-infrared (NIR) emissions have been rarely reported so far. Here, inspired by the chromophore chemical structure of fluorescent proteins, we designed and synthesized a series of styrene oxazolone dyes (SODs) with simple synthetic methods, which show NIR emissions (>650 nanometers) with long Stokes shift (ranged from 136 to 198 nanometers) and small molecular weight (<450 daltons). The most promising SOD9 shows rapid renal excretion and blood-brain barrier passing properties. After functioning with the mitochondrial-targeted triphenylphosphonium (TPP) group, the resulting SOD9-TPP can be engineered for head-neck tumor imaging, fluorescence image-guided surgery, brain neuroimaging, and on-site pathologic analysis. In summary, our findings add an essential small molecular dye category to the classical dyes.

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

[Lead compound optimization strategy (2)--structure optimization strategy for reducing toxicity risks in drug design].

Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.

[Application of methyl in drug design].

The methyl group plays an important role in the rational drug design. Introducing methyl into small molecules has become an important strategy of lead compound optimization. The application of methyl in drug design is reviewed in this paper. Methyl can modulate the physicochemical, pharmacodynamic, and pharmacokinetic properties by ortho effect, inductive effect, and conformational effect. It also improves the metabolic stability as a soft metabolic point. In addition, introducing methyl into drug molecules can also be applied as a strategy in new uses of old drugs and generate me-too drugs.

Enantioselective synthesis of 2-substitued-tetrahydroisoquinolin-1-yl glycine derivatives via oxidative cross-dehydrogenative coupling of tertiary amines and chiral nickel(II) glycinate.

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel(II) glycinate using o-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives.

Highly diastereoselective synthesis of 3-indolylglycines via an asymmetric oxidative heterocoupling reaction of a chiral nickel(II) complex and indoles.

The asymmetric synthesis of 3-indolylglycine derivatives was achieved by an oxidative heterocoupling reaction. This method for the selective C-3 functionalization of unprotected indoles with the chiral equivalent of a nucleophilic glycine nickel(II) complex afforded adducts with high diastereoselectivities. The decomposition of adducts readily afforded 3-indolylglycine derivatives in high yields.

Synthesis of polysubstituted ß-amino cyclohexane carboxylic acids via Diels-Alder reaction using Ni(II)-complex stabilized ß-alanine derived dienes.

This paper describes the design and synthesis of a new class of ß-alanine derived dienes stabilized by Ni(II)-complex. Preliminary study of their Diels-Alder cycloaddition reactions with several types of dienophiles demonstrates their significant synthetic potential for the preparation of various polyfunctional ß-aminocyclohexane carboxylic acids.

Improved synthesis of rupintrivir.

An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (l-glutamic acid, d-4-fluorophenylalanine, and l-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.

Preparation of α-alkyl-ß-amino acids via ß-alanine Ni(II) complex.

A new ß-amino acrylic acid Ni(II) complex has been developed and used for the synthesis of α-alkyl-ß-amino acids via alkylation with alkyl halides under operationally convenient conditions. The pivotal α-alkylated intermediate can be converted into the corresponding α-alkyl-ß-amino acids via two steps with a wide range of substituents.

Enterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design.

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of hand, foot, and mouth disease (HFMD), which is prevalent in Asia. Thus far, there are no prophylactic or therapeutic measures against HFMD. The 3C proteases from EV71 and CVA16 play important roles in viral replication and are therefore ideal drug targets. By using biochemical, mutational, and structural approaches, we broadly characterized both proteases. A series of high-resolution structures of the free or substrate-bound enzymes were solved. These structures, together with our cleavage specificity assay, well explain the marked substrate preferences of both proteases for particular P4, P1, and P1' residue types, as well as the relative malleability of the P2 amino acid. More importantly, the complex structures of EV71 and CVA16 3Cs with rupintrivir, a specific human rhinovirus (HRV) 3C protease inhibitor, were solved. These structures reveal a half-closed S2 subsite and a size-reduced S1' subsite that limit the access of the P1' group of rupintrivir to both enzymes, explaining the reported low inhibition activity of the compound toward EV71 and CVA16. In conclusion, the detailed characterization of both proteases in this study could direct us to a proposal for rational design of EV71/CVA16 3C inhibitors.

Highly diastereo- and enantioselective synthesis of syn-ß-substituted tryptophans via asymmetric Michael addition of a chiral equivalent of nucleophilic glycine and sulfonylindoles.

The asymmetric synthesis of syn-ß-substituted tryptophan derivatives was carried out by the Michael addition of chiral equivalent of nucleophilic glycine with sulfonylindoles, and high diastereo- and enantioselectivities were achieved. The resulting adducts were readily converted to syn-ß-substituted tryptophans in 96% yield, indicating that the proposed method is a highly efficient route to chiral syn-ß-substituted tryptophans.

Synthesis of Pyrrolo[1,2-a]quinoxalines via gold(I)-mediated cascade reactions.

In this study, we developed an efficient tandem process of hydroamination and hydroarylation using a gold catalyst to enable and study the reactions between pyrrole-substituted anilines and alkynes. The gold(I)-catalyzed reactions were achieved in toluene at 80 °C over a reaction time of 1−6 h. These reactions are applicable to a variety of aromatic amino compounds and both the terminal and internal alkynes. Substituted pyrrolo[1,2-a]quinoxalines were obtained in moderate to excellent yields. A presumed mechanism involving intermolecular C−N bond formation and intramolecular nucleophilic reaction via a cationic gold complex has been proposed on the basis of the deuterium labeling studies.

Asymmetric synthesis of sterically and electronically demanding linear ω-trifluoromethyl containing amino acids via alkylation of chiral equivalents of nucleophilic glycine and alanine.

An operationally convenient, scalable asymmetric synthesis of linear, ω-trifluoromethyl-containing amino acids, which were not previously produced in their enantiomerically pure form, has been developed via alkylation of chiral equivalents of nucleophilic glycine and alanine. The simplicity of the experimental procedures and high stereochemical outcome (yields up to 90% and diastereoselectivity up to 99%) of the presented method render these fluorinated amino acids readily available for systematic medicinal chemistry studies and de novo peptide design.

Efficient synthesis of symmetrical alpha,alpha-disubstituted beta-amino acids and alpha,alpha-disubstituted aldehydes via dialkylation of nucleophilic beta-alanine equivalent.

Homologation of the nucleophilic beta-alanine equivalent beta-Ala Ni(II)-PABP [Ni(II) complex of beta-alanine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PABP), 1] via alkyl halide alkylation was systematically studied as a general method for preparing symmetrically alpha,alpha-disubstituted beta-amino acids. The dialkylation reactions could be easily performed and did not require inert atmosphere, dried solvents, and low temperatures, thereby affording the benefits of operationally convenient experimental procedure and high atom economy. Further, the methodology developed by us can also be used to generate symmetrical alpha,alpha-disubstituted aldehydes through an alternative decomposition method.