Elucidating Binding Selectivity in Cyclin-Dependent Kinases 4, 6, and 9: Development of Highly Potent and Selective CDK4/9 Inhibitors.

CDK4/6 inhibitors are effective in treating HR/HER2 breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting.

Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined.

Three-component modular synthesis of chiral 1,3-dioxoles a Rh-catalyzed carbenic olefination cascade.

The advance of organic synthesis and the discovery of novel chemical transformations are often propelled by the rational programming of various bond-forming mechanisms and sequences that involve delicate reactive intermediates. In this study, we present an innovative Rh(ii)-catalyzed asymmetric three-component cascade reaction involving I/P-hybrid ylides, aldehydes, and carboxylic acids for the synthesis of 1,3-dioxoles with moderate to good yields and high enantioselectivity. This method utilizes I/P-hybrid ylides as carbene precursors to form α-P-Rh-carbenes, which initiate the formation of carbonyl ylides, followed by stereoselective cyclization with carboxylate anions and an intramolecular Wittig olefination cascade, ultimately resulting in the modular assembly of chiral 1,3-dioxoles.

N-Heterocyclic Carbene-Catalyzed Asymmetric S2 Alkylation via Noncovalent Activation.

The field of asymmetric catalysis has been developed by exploring noncovalent interactions, particularly within N-heterocyclic carbene-mediated processes. Despite challenges due to the limited number of compatible electrophiles (predominantly π-acceptors), this study introduces the first asymmetric α-alkylation of 3-aryl oxindoles using C electrophiles. The innovative protocol integrates diverse oxindoles and alkyl, allyl, and propargyl electrophiles, achieving high yields and enantioselectivities.

Water mediated redox-neutral cleavage of arylalkenes via photoredox catalysis.

Cleavage of carbon-carbon bonds remains a challenging task in organic synthesis. Traditional methods for splitting C=C bonds into two halves typically involve non-redox (metathesis) or oxidative (ozonolysis) mechanisms, limiting their synthetic potential. Disproportionative deconstruction of alkenes, which yields one reduced and one oxidized fragment, remains an unexplored area.

Photochemical three-component assembly of tri-substituted oxazoles through a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade.

Construction of complex molecular skeletons with ubiquitous chemical feedstocks in a single transformation is highly appealing in organic synthesis. We report a novel visible-light-induced three-component reaction for the construction of complex 2,4,5-trisubstituted oxazoles, which are valuable in medicinal chemistry, from simple and readily available iodonium-phosphonium hybrid ylides, carboxylic acids, and nitriles. This reaction features a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade, in which a photo-generated α-phosphonium carbene acts as a sequence trigger.

Amide C-N bonds activation by A new variant of bifunctional N-heterocyclic carbene.

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C-N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield.

Enantioselective S 2 Alkylation of Homoenolates by N-Heterocyclic Carbene Catalysis.

The functionalization of the β-carbon of enals with electrophiles is a signature umpolung reactivity of N-heterocyclic carbene (NHC) derived homoenolates. However, only a limited number of electrophiles are shown to be compatible, with most of them being π-electrophiles. In this study, the successful enantioselective β-alkylation of homoenolates is reported using C electrophiles through an S 2 strategy.

Photoredox Cleavage of a C-C Bond in Aromatic Hydrocarbons.

Functionalizing molecules through the selective cleavage of carbon-carbon bonds is an attractive approach in synthetic chemistry. Despite recent advances in both transition-metal catalysis and radical chemistry, the selective cleavage of inert C-C bonds in hydrocarbon feedstocks remains challenging. Examples reported in the literature typically involve substrates containing redox functional groups or highly strained molecules.

The thiol-sulfoxonium ylide photo-click reaction for bioconjugation.

Visible-light-mediated methods were heavily studied as a useful tool for cysteine-selective bio-conjugation; however, many current methods suffer from bio-incompatible reaction conditions and slow kinetics. To address these challenges, herein, we report a transition metal-free thiol-sulfoxonium ylide photo-click reaction that enables bioconjugation under bio-compatible conditions. The reaction is highly cysteine-selective and generally finished within minutes with naturally occurring riboflavin derivatives as organic photocatalysts.

A Thioether-Catalyzed Cross-Coupling Reaction of Allyl Halides and Arylboronic Acids.

C(sp )-C(sp ) cross-coupling reactions are an indispensable tool for organic synthesis. In these reactions transition metals have been extensively employed to promote the formation of valuable carbon-carbon bonds. Herein, we report our recent discovery of a designer thioether as a highly active organocatalyst for reactions between an allyl bromide and an arylboronic acid.

An NHC-catalyzed [3+2] cyclization of β-disubstituted enals with benzoyl cyanides.

The NHC-catalyzed asymmetric [3+2] cyclization of benzoyl cyanides to homoenolate generated from enals was reported. This methodology leads to the efficient construction of a series of chiral cyclic compounds bearing vicinal quaternary stereocenters under mild reaction conditions. Additionally, the representative large-scale and derivatization reactions of the chiral cyclic products reveal the potential synthetic utility of this protocol.

Enantioselective synthesis of acyclic monohydrosilanes by steric hindrance assisted C-H silylation.

Herein, a rhodium-catalyzed desymmetrization of dihydrosilanes with heterocyclic compounds intermolecular dehydrogenative C-H silylation is developed. The strategy tolerates a variety of thianaphthene and thiophene derivatives, giving rise to a wide range of silicon-stereogenic acyclic monohydrosilanes. Several rare skeletons featuring bis-silicon-stereogenic centers were also designed to enhance the library's diversity further.

Enantioselective Seleno-Michael Addition Reactions Catalyzed by a Chiral Bifunctional N-Heterocyclic Carbene with Noncovalent Activation.

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β-stereogenic center. Despite its success in the formation of various asymmetric carbon-carbon and carbon-heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones.

N-Heterocyclic Carbene-Catalyzed 1,4-Alkylacylation of 1,3-Enynes.

The radical relay coupling reaction recently emerged as a powerful synthetic strategy for producing tetrasubstituted allenes. However, bond-forming processes involving the allenyl radical intermediate are mostly limited to those promoted by transition metals. In this report, we describe that a ketyl radical generated from single-electron oxidation of the Breslow intermediate is an excellent coupling partner of allenyl radicals.

Photo-induced energy transfer relay of N-heterocyclic carbene catalysis: an asymmetric α-fluorination/isomerization cascade.

The geometric configuration of olefin products is often driven by thermodynamic control in synthesis. Methods enabling switching of cis/trans selectivity are rare. Recently, photosensitized approaches have emerged as a powerful tool for accomplishing this task.

Direct Synthesis of Bicyclic Acetals via Visible Light Catalysis.

Polysubstituted bicyclic acetals are a class of privileged pharmacophores with a unique 3D structure and an adjacent pair of hydrogen bond acceptors. The key, fused acetal functionality is often assembled, via intramolecular cyclization, from linear substrates that are not readily available. Herein, we report a formal cycloaddition between cinnamyl alcohols and cyclic enol ethers under ambient photoredox catalysis conditions.

Enantioselective Intramolecular [2,3]-Sigmatropic Rearrangement of Aldehydes via a Sulfonium Enamine Intermediate.

The rearrangement of sulfur-containing aldehydes by using a sulfonium enamine intermediate as a formylcarbene mimetic is reported. This is an enantioselective, organocatalytic [2,3]-sigmatropic rearrangement enabling chiral cyclic sulfides bearing an α-quaternary chiral center to be prepared in high optical purity. The enantioselectivity is controlled with a cooperative organocatalyst pair consisting of a chiral amine and a chiral phosphoric acid (CPA).

Enantio- and Diastereoselective Hydrofluorination of Enals by N-Heterocyclic Carbene Catalysis.

In contrast to well-established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox-neutral conditions. Reported here is the highly enantio- and diastereoselective hydrofluorination of enals by an asymmetric β-protonation/α-fluorination cascade catalyzed by N-heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated.

Structure-Based Drug Design and Identification of HO-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo.

Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of HO-soluble and orally bioavailable hexacyclic CPT derivatives.

Aerobic Oxidation/Annulation Cascades through Synergistic Catalysis of RuCl and N-Heterocyclic Carbenes.

Cooperative catalysis combining a transition metal with an N-heterocyclic carbene is challenging due to strong binding of NHCs towards late transition metals. We report the first example of synergistic catalysis by a chiral NHC and a coordinatively unsaturated ruthenium compound. RuCl was found to mediate efficient aerobic oxidation of homoenolates generated from enals and the N-heterocyclic carbene.

Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species.

An enantioselective synthesis of β-chiral amides through asymmetric and redox-neutral hydroamidation of enals is reported. In this reaction, a chiral N-heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective β-protonation through proton-shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key β-chiral acyl species.