Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential.

Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties.

Structural insight into subunit F of respiratory chain complex I from Xanthomonas oryzae pv. oryzae inhibition by parthenolide.

Background: Bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious diseases of rice, and there is a lack of bactericides for controlling this disease. We previously found parthenolide (PTL) is a potential lead for developing bactericides against Xoo, and subunit F of respiratory chain complex I (NuoF) is an important target protein of PTL.

Identifying Dopamine D3 Receptor Ligands through Virtual Screening and Exploring the Binding Modes of Hit Compounds.

The dopamine D3 receptor (D3R) is an important central nervous system target for treating various neurological diseases. D3R antagonists modulate the improvement of psychostimulant addiction and relapse, while D3R agonists can enhance the response to dopaminergic stimulation and have potential applications in treating Parkinson’s disease, which highlights the importance of identifying novel D3R ligands. Therefore, we performed auto dock Vina-based virtual screening and D3R-binding-affinity assays to identify human D3R ligands with diverse structures.

Identification of TUL01101: A Novel Potent and Selective JAK1 Inhibitor for the Treatment of Rheumatoid Arthritis.

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound ) based on a triazolo[1,5-]pyridine core of filgotinib. It showed excellent potency on JAK1 with an IC value of 3 nM and exhibited more than 12-fold selectivity for JAK2 and TYK2.

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors.

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors.

Transition-metal-free, one-pot synthesis of benzoxaboroles from -bromobenzaldehydes visible-light-promoted borylation.

A novel and simple one-pot stepwise method to synthesize benzoxaboroles was demonstrated. This step-by-step synthetic method includes photocatalytic boronization with phenothiazine as a photocatalyst and sequential water-induced reduction in the presence of bis(pinacolato)diboron. A series of -bromobenzaldehydes were well-tolerated under the standard conditions.

Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2.

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors.

Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure.

Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science.

Separation of eight bedaquiline analogue diastereomers by HPLC on an immobilized polysaccharide-based chiral stationary phase.

The high-performance liquid chromatography (HPLC) is a powerful method in the area of stereoisomer separation. In this study, separation of eight bedaquiline analogue diastereomers (compounds 1-8) was first examined on a cellulose tris-(3,5-dichlorophenylcarbamate) chiral stationary phase, ie, Chiralpak IC in the normal phase mode. The influences of organic modifier types, alcohol content, and column temperature on diastereoseparation were evaluated.

Design, synthesis and antifungal evaluation of borrelidin derivatives.

Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis.

Diagnostic absolute configuration determination of clavulanate potassium: A comprehensive investigation of chiroptical spectroscopies and theoretical calculations.

Clavulanate potassium (CP) is a classic β-lactamase inhibitor, which is extensively used as a combination drug in antibiotics therapy. As a chiral drug, CP is the only effective stereoisomer revealing prominent activities. To determine the chirality of CP efficiently, we provide an accurate and convenient method based on the comprehensive investigation of circular dichroism spectra and theoretical calculations.

A Class of Amide Ligands Enable Cu-Catalyzed Coupling of (Hetero)aryl Halides with Sulfinic Acid Salts under Mild Conditions.

The amide derived from 4-hydroxy-l-proline and 2,6-dimethylaniline is a powerful ligand for Cu-catalyzed coupling of (hetero)aryl halides with sulfinic acid salts, allowing the formation of a wide range of (hetero)aryl sulfones from the corresponding (hetero)aryl halides at considerably low catalytic loadings. The coupling of (hetero)aryl iodides and sodium methanesulfinate proceeds at room temperature with only 0.5 mol % CuI and ligand, representing the first example for Cu-catalyzed arylation at both low catalytic loading and room temperature.

Study on the HPLC-based separation of some ezetimibe stereoisomers and the underlying stereorecognition process.

The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode.

Effectively enhancing the enantioseparation ability of β-cyclodextrin derivatives by de novo design and molecular modeling.

Rational engineering of native β-CD as an ideal chiral selector for a definite analyte in capillary electrophoresis represents a challenge in separation science. Herein, a rational and systematic strategy that combines the de novo design and molecular modeling is firstly described to expedite the manipulation and selection of effective selector for enantioseparation in capillary electrophoresis. Using β-adrenoreceptor agonists as model analytes, we demonstrate how this strategy efficiently improves the enantiorecognition in chiral discrimination sites of inclusion complexes.

Comparison of three S-β-CDs with different degrees of substitution for the chiral separation of 12 drugs in capillary electrophoresis.

Three kinds of sulfated β-cyclodextrin (S-β-CD), including a single isomer, heptakis-6-sulfato-β-cyclodextrin (HS-β-CD), degree of substitution (DS) of 7, which was synthesized in our laboratory and another two commercialized randomly substituted mixtures, a sulfated β-cyclodextrin with DS of 7 to 11, as well as a highly sulfated-β-cyclodextrin with DS of 12 to 15, were used for the enantioresolution of 12 drugs (the β-blockers, phenethylamines, and anticholinergic agents) in capillary electrophoresis. The enantioseparation under varying concentrations of S-β-CD and background electrolyte pH were systematically investigated and compared. Based on the experimental results, the effect of the nature of S-β-CD and analyte structure on the enantioseparation is discussed.

New Metabolites and Bioactive Chlorinated Benzophenone Derivatives Produced by a Marine-Derived Fungus Pestalotiopsis heterocornis.

Four new compounds, including two isocoumarins, pestaloisocoumarins A and B (, ), one sesquiterpenoid degradation, isopolisin B (), and one furan derivative, pestalotiol A (), together with one known isocoumarin, gamahorin (), and three chlorinated benzophenone derivatives, pestalachloride B (), pestalachloride E () and a mixture of pestalalactone atropisomers (), were isolated from a culture of the fungus associated with sponge . These new chemical structures were established using NMR and MS spectroscopic data, as well as single-crystal X-ray crystallographic analysis and CD Cotton effects. All of the isolated compounds were evaluated for their antimicrobial and cytotoxic activities.

Biotransfomation of cyperenoic acid by Cunninghamella elegans AS 3.2028 and the potent anti-angiogenic activities of its metabolites.

Cyperenoic acid (1) is one of the major sesquiterpenes isolated from Croton crassifolius, which exhibited potent anti-angiogenic activity. Traditional structural modification of 1 is difficult to perform by chemical technology due to the remarkable stability of the patchoulane skeleton. In order to overcome chemical synthesis difficulties and obtain structurally diverse derivations, microbial transformation of 1 by using Cunninghamella elegans AS 3.

N-terminal truncated carboxypeptidase E expression is associated with poor prognosis of lung adenocarcinoma.

Lung cancer is a malignant tumor with high morbidity and mortality rates. To date, no suitable molecular diagnostic tool to predict disease recurrence and metastasis has been identified. The current study aimed to evaluate the potential of N-terminal truncated carboxypeptidase E (CPEΔN) to predict the recurrence and metastasis of lung adenocarcinoma.

Two new compounds from Atractylodes macrocephala with neuroprotective activity.

In the present study, two new compounds, together with six known compounds, were isolated from rhizome of Atractylodes macrocephala Koidz by a series of silica gel, ODS column chromatography, and preparative HPLC. Their structures were characterized as atractylenolide II (1), atractylenolide I (2), biepiasterolid (3), isoatractylenolide I (4), atractylenolide III (5), 3β-acetoxyl atractylenolide I (6), (4E,6E,12E)-tetradeca-4,6,12-triene-8,10-diyne-13,14-triol (7), (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol (8) on the basis of 1D, 2D NMR, and circular dichroism analyses. Among them, compounds 6 and 8 were novel compounds.

Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents.

A series of bedaquiline analogs containing H-bond donors were designed as anti-Mycobacterium tuberculosis drugs. A pair of diastereoisomers (R/S- and S/S-isomers) was selected from these designed compounds for synthetic and stereochemical research. The title compounds were synthesized from chiral precursors for the first time and the absolute configurations (ACs) were determined by electronic circular dichroism (ECD) with quantum chemical calculations.

Synthesis, Crystal Structure, Absolute Configuration and Antitumor Activity of the Enantiomers of 5-Bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide.

Pyridinesulfonamide is an important fragment which has a wide range of applications in novel drugs. R- and S-isomers of 5-bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide have been synthesized, and the stereostructures have been researched. Single crystals of both compounds were obtained for X-ray analysis, and the absolute configurations (ACs) have been further confirmed by electronic circular dichroism (ECD), optical rotation (OR) and quantum chemical calculations.

Separation of folinic acid diastereomers in capillary electrophoresis using a new cationic β-cyclodextrin derivative.

A method for the separation of folinic acid diastereomers by capillary electrophoresis in chiral separation media was developed. Aiming to achieve a good separation of the anionic analytes, a newly synthesized cationic β-cyclodextrin derivative, mono-6-deoxy-6-piperdine-β-cyclodextrin, was applied as the chiral selector. The effect of background electrolyte pH, the concentration of the cyclodextrin additive, and organic modifier on the separation was investigated.

Density functional theory (DFT) and natural bond orbital (NBO) study of vibrational spectra and intramolecular hydrogen bond interaction of L-ornithine-L-aspartate.

In this study, exhaustive conformations of (S)-4-amino-4-carboxybutan-1-aminium (S)-3-amino-3-carboxypropanoate (LOLA) have been scanned. Experimental and theoretical studies on the structure and vibrations of the title compound are presented. The optimized molecular structure, vibrational wavenumbers, Mulliken atomic charges, natural bond orbital (NBO) and molecular electrostatic potential studies have been performed by density functional theory (DFT) using B3LYP method with the 6-311++G(d,p) basis set.

Quantitative prediction of enantioseparation using β-cyclodextrin derivatives as chiral selectors in capillary electrophoresis.

β-Cyclodextrin derivatives as chiral selectors are becoming increasingly important for enantioseparations in capillary electrophoresis (CE). Nevertheless, there are some enormous challenges in choosing effective selectors from a variety of compounds, and up to now no systematic quantitative studies for predicting the possibility of enantiomeric separation before CE experiments have been reported. In this paper, in order to resolve previous confusions, we investigated the enantioseparations of ten chiral drugs using a method of combining experiments with theoretical calculations.

Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors.

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 = 1.