Visible light-induced controlled release and biological evaluation of bismuth sulfide quantum dots and silver nanoparticles co-sensitized titanium dioxide nanotubes.

Controlled drug delivery has attracted significant attention because of its ability to release therapeutic agents at specific times and locations. Titanium dioxide nanotubes (TNTs), which are known for their unique tubular morphology, large surface area and excellent biocompatibility, have been widely investigated as drug carriers. However, their application in light-induced drug release is limited by their reliance on ultraviolet (UV) light.

Tandem SAr/Aldol Condensation of Oxindoles with -Haloacetophenones Enables Modular Assembly of 2,3-Fused Indolines Bearing a Quaternary Carbon.

Described herein is a novel base-promoted [4 + 2] annulation reaction of 3-methyl-indolin-2-ones with -haloacetophenones, which enables the modular and reliable synthesis of 2,3-fused indolines bearing a quaternary carbon. Two C-C bonds can be successively constructed through a tandem sequence involving base-promoted SAr and aldol condensation. This protocol is highlighted by transition metal-free conditions, high efficiency, and simple operation.

Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13.

Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells.

Application of deuterium in research and development of drugs.

Deuterium is gaining increased attention and utilization due to its unique physical and chemical properties. Deuteration has the unique benefit of positively impacting metabolic fate of pharmacologically active compounds without altering their chemical structures, physical properties, or biological activity and selectivity. In these favorable cases, deuterium substitution can in principle improve the pharmacokinetic properties and safety of therapeutic agents.

Application of Transformers to Chemical Synthesis.

Efficient chemical synthesis is critical for the production of organic chemicals, particularly in the pharmaceutical industry. Leveraging machine learning to predict chemical synthesis and improve the development efficiency has become a significant research focus in modern chemistry. Among various machine learning models, the Transformer, a leading model in natural language processing, has revolutionized numerous fields due to its powerful feature-extraction and representation-learning capabilities.

Efficient Iron-Catalyzed Site/Regioselective Phosphinoylation of Carbohydrates.

The selective incorporation of phosphorus groups into sugar molecules holds substantial synthetic and biological significance, yet this area of research remains largely unexplored. In this study, we successfully devised a novel method employing an efficient Fe(III) catalyst for achieving site/regioselective phosphorylation/phosphinoylation of carbohydrates. This methodology boasts several merits, including mild reaction conditions, the employment of cost-effective and readily available catalysts, and exceptional selectivity.

Convergent Assembly of 1,4-Benzothiazide Spiroindolinones via [4 + 2] Spiroannulation Under Open-Air Conditions.

This report discloses a transition-metal-free [4 + 2] spirocyclization of isatin-derived β-silylcarbinols and 2-aminobenzenethiols, providing a facile approach to 1,4-benzothiazide spiroindolinones in decent yields. Control experiments indicate that 3-methylene oxindoles and disulfides are key intermediates in this tandem reaction. Moreover, the resulting products can be facilely converted into pharmaceutically significant sulfone and sulfoxide scaffolds, which further demonstrates the potential utility of this protocol.

Design, synthesis, and biological evaluation of dithiocarbamate derivatives as SARS-CoV-2 M inhibitors.

SARS-CoV-2 continues to mutate, spread, and impact public health and daily life. The main protease (M) is essential for the replication and maturation of SARS-CoV-2, making it an ideal target for anti-coronaviral drug discovery and development due to its high conservation and lack of homologous proteases in humans. Herein, we designed and synthesized a series of dithiocarbamate derivatives as potent SARS-CoV-2 M inhibitors.

Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors (2019-2023).

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a vital cornerstone of highly active antiretroviral therapy (HAART) regimens, owing to their unique antiviral activity, low toxicity and high specificity. Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine and rilpivirine, have attracted extensive attention due to their high anti-HIV potency. However, rapid emergence of resistant mutations, suboptimal pharmacokinetics (PK), and toxicity remain significant challenges.

Regioselective Cleavage and Reconfiguration of C-S Bonds with Diazo Compounds.

A coupling reaction between diazo compounds and phenyl benzyl sulfide catalyzed by TfOH has been reported. This reaction can synthesize important α-arylthio carbonyl compounds via regioselective cleavage and reconfiguration of C-S bonds, and various functional groups were tolerant to the reaction conditions. Mechanistic studies have conclusively established that the pivotal intermediate in the reaction was meticulously investigated through spectroscopic evidence, complemented by rigorous control experiments.

Al(OTf)-Catalyzed Regioselective N-Arylation of Tetrazoles with Diazo Compounds.

Regioselective methods to access alkylated tetrazoles still remain a challenging goal. Herein, we describe a novel regioselective protocol for N-arylation of tetrazoles with diazo compounds using inexpensive Al(OTf). This reaction could be conducted under mild conditions to access a diverse array of alkylated tetrazoles with 2-substituted tetrazoles as the major products, demonstrating a comprehensive range of substrate compatibility and excellent functional group compatibility.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer.

Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review.

The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (M) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body.

Synthesis of 2,4-Disubstituted Oxazoles and Thiazoles via Brønsted Acid-Catalyzed Cyclization of α-diazoketones with Amides.

A novel method is described for the synthesis of 2,4-disubstituted oxazole and thiazole derivates via the coupling of α-diazoketones with (thio)amides or thioureas using trifluoromethanesulfonic acid (TfOH) as a catalyst. This protocol is characterized by mild reaction conditions, metal-free, and simplicity and also features good functional group tolerance, good to excellent yields, and a broad substrate scope with more than 40 examples. Experimental studies suggest a mechanism involving 2-oxo-2-phenylethyl trifluoromethanesulfonate as the key intermediate.

Chemodivergent Synthesis of Sulfonamide and Sulfones from -Tosylhydrazones by Switching Catalyst and Temperature.

A catalyst- and temperature-controlled selective synthesis of sulfonamide and sulfones from -tosylhydrazones and MBH carbonates has been developed. The use of palladium catalysts exclusively leads to sulfonamide products at room temperature, whereas the selective synthesis of sulfones is dominant for a temperature-controlled coupling reaction without palladium catalysis. Importantly, the catalyst- or temperature-controlled reaction exhibits high nucleophilicity rather than carbene reactivity in these transformations.

Quinolines and isoquinolines as HIV-1 inhibitors: Chemical structures, action targets, and biological activities.

Human immunodeficiency virus type 1 (HIV-1), a lentivirus that causes acquired immunodeficiency syndrome (AIDS), poses a serious threat to global public health. Since the advent of the first drug zidovudine, a number of anti-HIV agents acting on different targets have been approved to combat HIV/AIDS. Among the abundant heterocyclic families, quinoline and isoquinoline moieties are recognized as promising scaffolds for HIV inhibition.

Iridium-Catalyzed Intramolecular Asymmetric Allylation of Vinyl Benzoxazinones for the Synthesis of Chiral 4-3,1-Benzoxazines via Kinetic Resolution.

Chiral benzoxazinones and 4-3,1-benzoxazines as important motifs are widely found in abundant pharmaceuticals and biological molecules. We herein successfully developed the first kinetic resolution (KR) process of racemic benzoxazinones through Ir-catalyzed asymmetric intramolecular allylation, furnishing a wide range of chiral benzoxazinones and 4-3,1-benzoxazines with excellent results via outstanding KR performances (with the factor up to 170). This protocol exhibited broad substrate scope generality and good functional group tolerance, and the chiral 4-3,1-benzoxazine products could be readily transformed to other useful optically active heterocycles.

E3 ligase ligand optimization of Clinical PROTACs.

Proteolysis targeting chimeras (PROTACs) technology can realize the development of drugs for non-druggable targets that are difficult to achieve with traditional small molecules, and therefore has attracted extensive attention from both academia and industry. Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only was based on VHL ligand.

Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents.

The α- and β-tubulins are the major polypeptide components of microtubules (MTs), which are attractive targets for anticancer drug development. Indole derivatives display a variety of biological activities including antitumor activity. In recent years, a great number of indole derivatives as tubulin polymerization inhibitors have sprung up, which encourages medicinal chemists to pursue promising inhibitors with improved antitumor activities, excellent physicochemical, pharmacokinetic and pharmacodynamic properties.

Advances in the development of HIV integrase strand transfer inhibitors.

HIV-1 integrase (IN) is a key enzyme in viral replication that catalyzes the covalent integration of viral cDNA into the host genome. Currently, five HIV-1 IN strand transfer inhibitors (INSTIs) are approved for clinical use. These drugs represent an important addition to the armamentarium for antiretroviral therapy.

Recent discoveries in HIV-1 reverse transcriptase inhibitors.

HIV-1 reverse transcriptase inhibitors (RTIs) are indispensable components of highly active antiretroviral therapy (HAART), which has achieved great success in controlling AIDS epidemic in reducing drastically the morbidity and mortality of HIV-infected patients. RTIs are divided into two categories, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). In this review, the recent discoveries in NRTIs and NNRTIs, including approved anti-HIV drugs and noteworthy drug candidates in different development stages, are summarized, and their future direction is prospected.

Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.

Background: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC.

Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K.

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC values ranging from 1.