Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach.

Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.

Synthesis, Characterization, Biological Evaluation and DNA Interaction Studies of 4-Aminophenol Derivatives: Theoretical and Experimental Approach.

In the present study, five 4-aminophenol derivatives (4-chloro-2-(((4-hydroxyphenyl)imino)methyl)phenol(S-1), 4-((4-(dimethylamino)benzylidene)amino)phenol(S-2), 4-((3-nitrobenzylidene)amino)phenol(S-3), 4-((thiophen-2-ylmethylene)amino)phenol(S-4) and 4-(((E)-3-phenylallylidene)amino)phenol(S-5)) were synthesized and characterized by FT-IR, 1H-NMR, 13C-NMR and elemental analyses. The synthesized compounds were tested for their antimicrobial (Gram-positive and Gram-negative bacteria and Saccharomyces cervesea fungus) and antidiabetic (α-amylase and α-glucosidase inhibitory) activities. All the compounds showed broad-spectrum activities against the Staphylococcus aureus (ATCC 6538), Micrococcus luteus (ATCC 4698), Staphylococcus epidermidis (ATCC 12228), Bacillus subtilis sub. sp spizizenii (ATCC 6633), Bordetella bronchiseptica (ATCC 4617) and Saccharomyces cerevisiae (ATCC 9763) strains. The newly synthesized compounds showed a significant inhibition of amylase (93.2%) and glucosidase (73.7%) in a concentration-dependent manner. Interaction studies of Human DNA with the synthesized Schiff bases were also performed. The spectral bands of S-1, S-2, S-3 and S-5 all showed hyperchromism, whereas the spectral band of S-4 showed a hypochromic effect. Moreover, the spectral bands of the S-2, S-3 and S-4 compounds were also found to exhibit a bathochromic shift (red shift). The present studies delineate broad-spectrum antimicrobial and antidiabetic activities of the synthesized compounds. Additionally, DNA interaction studies highlight the potential of synthetic compounds as anticancer agents. The DNA interaction studies, as well as the antidiabetic activities articulated by the molecular docking methods, showed the promising aspects of synthetic compounds.

Modulators of CFTR. Updates on clinical development and future directions.

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Polymersome-Based Modular Nanoreactors with Size-Selective Transmembrane Permeability.

Polymersome nanoreactors encapsulating the enzymes or particulate catalysts attract interest because of their potential use as modular reactors to synthesize complex compounds via a cascade of chemical reactions in a single batch. To achieve these goals, a key requirement is the tunable permeability of the polymersome membrane, which allows the size-selective transportation of reagents and products while protecting the encapsulated catalysts during the chemical reaction. We report here a stimuli-responsive route for controlling the permeability of the polymersomes of the binary blend of poly(ethylene glycol)-b-polystyrene (PEG-b-PS) and poly(ethylene glycol)-b-poly(acrylbenzylborate) (PEG-b-PABB). The presence of H2O2 (1 mM) in the medium (0.1 M PBS, pH 7.4) triggers the oxidation of benzyl borate pendants of PABB to form poly(acrylic acid) (PAA). This transformation results in the perforation of the compartmentalizing membrane of polymersomes by the dissolution of PEG-b-PAA domains embedded in the inert PEG-b-PS matrix. By controlling the composition of the stimuli-responsive block copolymer, the polymersomes of the binary blend exhibit size-selective permeability without losing the structural integrity. Release of fluorescent guests with different sizes (fluorescein, PEG2k-Cm, PEG5k-Rho) can be controlled by tuning the composition (PEG-b-PS/PEG-b-PABB = 100/0-80/20) of blended polymersomes. Selective permeability of the membrane provides protection of the encapsulated enzymes from external proteases present in the medium, resulting in the one-pot synthesis of small molecules via cascades of chemical reactions. The nanoparticular catalysts are also encapsulated within the permeable polymersomes, serving as modular reactors for the conversion of organic compounds via a cascade of reactions.

Central-radial bi-porous nanocatalysts with accessible high unit loading and robust magnetic recyclability for 4-nitrophenol reduction.

Central-radial bi-porous nanocatalysts were synthesized by derivation from dendritic porous supports with hierarchical inorganic functional layers. The nanostructure exhibited a high unit loading capacity, accessible internal catalytic sites and protective mesoporous shell encapsulation. The nanocatalysts were utilized for efficient and stable heterogeneous catalytic reduction of 4-nitrophenol to 4-aminophenol with robust magnetic recyclability.

Lumacaftor-ivacaftor in the treatment of cystic fibrosis: design, development and place in therapy.

Lumacaftor-ivacaftor is a combination of two small molecule therapies targeting the basic defect in cystic fibrosis (CF) at a cellular level. It is a precision medicine and its effects are specific to individuals with two copies of the p.Phe508del gene mutation. The drug combination works by restoring functioning CF transmembrane conductance regulator (CFTR) protein in cell surface membranes and was the first CFTR modulator licensed for the homozygous p.Phe508del genotype. The drug is a combination of a CFTR corrector and potentiator. Lumacaftor, the corrector, works by increasing the trafficking of CFTR proteins to the outer cell membrane. Ivacaftor, the potentiator, works by enabling the opening of what would otherwise be a dysfunctional chloride channel. In vivo lumacaftor-ivacaftor improves Phe508del-CFTR activity in airways, sweat ducts and intestine to approximately 10-20% of normal CFTR function with greater reductions in sweat chloride levels in children versus adults. Its use results in a modest improvement in lung function and a decreased rate of subsequent decline. Perhaps more importantly, those treated report increased levels of well-being and their rate of respiratory exacerbations is significantly improved. This review traces the development and use of this combination of CFTR modulators, the first licensed drug for treating the homozygous p.Phe508del CF genotype at the intracellular level by correcting the protein defect.

Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation.

The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.

A new composite based on graphene oxide-poly 3-aminophenol for solid-phase microextraction of four triazole fungicides in water and fruit juices prior to high-performance liquid chromatography analysis.

An environmentally friendly method which is based on preparation and use of a new composite consisting of poly 3-aminophenol and graphene oxide for solid-phase microextraction of triazole fungicides from natural water and juices is introduced. The composite was synthesized by in-situ polymerization of 3-aminophenol and graphene oxide in weak alkaline media. By using the obtained results from the characterization, a suitable mechanism for polymerization and a proper structure for the polymer were proposed. Under optimal conditions, there are linear relationships between concentration of triazoles and their HPLC peak areas in the range of 0.5-100 µg L-1. The recovery percentages, pre-concentration factors and LOQ for all triazoles were 95.2-98.0%, about 200 and 0.2-0.4 µg L-1, respectively. The offered method was applied for extraction and determination of triazoles from natural water, some juices and it represents a promising alternative method for analysis of triazoles.

Fluorescent probe for sensitive discrimination of Hcy and Cys/GSH in living cells via dual-emission.

Abnormal levels of Cys, Hcy and GSH are associated with various diseases, thus monitoring biothiols is of great significance. In this work, a dual-emission responsive near-infrared fluorescent probe NIR-NBD for detecting Hcy and Cys/GSH was developed based on the conjugation of a dicyanoisophorone based fluorophore (NIR-OH) and 7-nitrobenzofurazan (NBD). To our surprise, the addition of Hcy induced significant fluorescence enhancement at both 549 and 697 nm; while Cys/GSH resulted in major fluorescence emission at 697 nm. The detection limit was determined to be 33.2 nM for Cys, 33.5 nM for Hcy, and 34.4 nM for GSH. Therefore, the probe can be used for discriminative detection of Hcy and Cys/GSH. Moreover, fluorescence imaging of HeLa cells indicated that the probe was cell membrane permeable and could be used for visualizing Hcy and Cys/GSH in living cells.

A Catch-and-Release Approach to Selective Modification of Accessible Tyrosine Residues.

The tyrosine side chain is amphiphilic leading to significant variations in the surface exposure of tyrosine residues in the folded structure of a native sequence protein. This variability can be exploited to give residue-selective functionalization of a protein substrate by using a highly reactive diazonium group tethered to an agarose-based resin. This novel catch-and-release approach to protein modification has been demonstrated for proteins with accessible tyrosine residues, which are compared with a control group of proteins in which there are no accessible tyrosine residues. MS analysis of the modified proteins showed that functionalization was highly selective, but reactivity was further attenuated by the electrostatic environment of any individual residue. Automated screening of PDB structures allows identification of potential candidates for selective modification by comparison with the accessibility of the tyrosine residue in a benchmark peptide (GYG).

An integrated nanocatalyst combining enzymatic and metal-organic framework catalysts for cascade degradation of organophosphate nerve agents.

An integrated nanocatalyst (INC), denoted OPH@MIL-100(Fe), was synthesized by immobilizing a biocatalyst onto a metal-organic framework (MOF)-based catalyst, which can cascadingly degrade organophosphate nerve agents to 4-aminophenol (4-AP) and result in a sharp decrease of their toxicity up to 208-fold.

A green strategy for the synthesis of sulfone derivatives of p-methylaminophenol: Kinetic evaluation and antibacterial susceptibility.

This is one of the few examples in which the diverse products have been synthesized just by changing the applied potential. The synthesis of sulfonyl derivatives of p-methylaminophenol were carried out by reaction of the electrogenerated p-methylquinoneimine with sulfinic acids. Various types of mono (MSP), bis (BSP) and tris (TSP) sulfonyl p-methyl aminophenols were obtained by changing the electrode potential, in one pot under green conditions. The mono sulfonyl-p-(methylamino)phenol derivatives (MSP) were assessed for their in vitro antibacterial activity against the gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) strains. It was found that the tested compounds were more active against Staphylococcus aureus than Escherichia coli. We also found that the antimicrobial activity of MSP derivatives to vary in the order MSP4 (R = CH3) > MSP1 (R = p-tolyl) ≈ MSP2 (R = phenyl) > MSP3 (R = p-ClC6H4). Moreover, the observed homogeneous rate constants (k obs) of the reaction of p-methyl quinoneimine with sulfinic acids were estimated in various pH values, based on the EC and ECEC mechanisms, by comparing the simulated cyclic voltammograms with the experimental ones.

Reaction of bis[(2-chlorocarbonyl)phenyl] Diselenide with Phenols, Aminophenols, and Other Amines towards Diphenyl Diselenides with Antimicrobial and Antiviral Properties.

A reaction of bis[(2-chlorocarbonyl)phenyl] diselenide with various mono and bisnucleophiles such as aminophenols, phenols, and amines have been studied as a convenient general route to a series of new antimicrobial and antiviral diphenyl diselenides. The compounds, particularly bis[2-(hydroxyphenylcarbamoyl)]phenyl diselenides and reference benzisoselenazol-3(2H)-ones, exhibited high antimicrobial activity against Gram-positive bacterial species (Enterococcus spp., Staphylococcus spp.), and some compounds were also active against Gram-negative E. coli and fungi (Candida spp., A.niger). The majority of compounds demonstrated high activity against human herpes virus type 1 (HHV-1) and moderate activity against encephalomyocarditis virus (EMCV), while they were generally inactive against vesicular stomatitis virus (VSV).

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin.

Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.

Improved fluorescence assays to measure the defects associated with F508del-CFTR allow identification of new active compounds.

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for a Cl-/HCO3 - channel. F508del, the most common CF-associated mutation, causes both gating and biogenesis defects in the CFTR protein. This paper describes the optimization of two fluorescence assays, capable of measuring CFTR function and cellular localization, and their use in a pilot drug screen. EXPERIMENTAL APPROACH: HEK293 cells expressing YFP-F508del-CFTR, in which halide sensitive YFP is tagged to the N-terminal of CFTR, were used to screen a small library of compounds based on the VX-770 scaffold. Cells expressing F508del-CFTR-pHTomato, in which a pH sensor is tagged to the fourth extracellular loop of CFTR, were used to measure CFTR plasma membrane exposure following chronic treatment with the novel potentiators. KEY RESULTS: Active compounds with efficacy ~50% of VX-770, micromolar potency, and structurally distinct from VX-770 were identified in the screen. The F508del-CFTR-pHTomato assay suggests that the hit compound MS131A, unlike VX-770, does not decrease membrane exposure of F508del-CFTR. CONCLUSIONS AND IMPLICATIONS: Most known potentiators have a negative influence on F508del-CFTR biogenesis/stability, which means membrane exposure needs to be monitored early during the development of drugs targeting CFTR. The combined use of the two fluorescence assays described here provides a useful tool for the identification of improved potentiators and correctors. The assays could also prove useful for basic scientific investigations on F508del-CFTR, and other CF-causing mutations.

Radical scavenging and antibacterial activity of caffemides against gram positive, gram negative and clinical drug resistance bacteria.

A new series of caffemide were synthesized and their antioxidant and antibacterial activities were explored. Antioxidant and antibacterial activities were measured of different structures of caffemide containing different functional groups. Anti-oxidative caffemides 1b and 1g showed significantly higher activity against different bacteria with MIC values less than 50µg/ml. These anti-oxidative and antibacterial properties of caffemides might be helpful for the treatment of secondary infections and discovery of new antibiotics.

A Mutasynthetic Library of Platensimycin and Platencin Analogues.

Inactivation of ptmB1, ptmB2, ptmT2, or ptmC in Streptomyces platensis SB12029, a platensimycin (PTM) and platencin (PTN) overproducer, revealed that PTM and PTN biosynthesis features two distinct moieties that are individually constructed and convergently coupled to afford PTM and PTN. A focused library of PTM and PTN analogues was generated by mutasynthesis in the ΔptmB1 mutant S. platensis SB12032. Of the 34 aryl variants tested, 18 were incorporated with high titers.

Gold nanostars: Benzyldimethylammonium chloride-assisted synthesis, plasmon tuning, SERS and catalytic activity.

Fabrication of Au nanostars (AuNSs) can expand the application range of Au nanoparticles because of their high electron density and localized surface plasmon resonance (LSPR) on branches. Exploiting this potential requires further refinement of length of the branches and radius of their tips. To this end, we successfully synthesized AuNSs with uniform and sharply-pointed branches by combining benzyldimethylammonium chloride (BDAC) and cetyltrimethylammonium bromide (CTAB) at low BDAC/CTAB ratios. Once mixed with CTAB, BDAC lowers the critical micelle concentration (CMC) for quick formation of the micelles, which provides favorable growth templates for AuNSs formation. Besides, BDAC increases the concentration of Cl(-), which favors Ag(+) in adsorbing on Au facets. This feature is crucial for the yield boosting and synergic shape control of AuNSs regardless of types of Au seeds used. Use of less amounts of seeds as the center of nucleation benefited sharper and longer growth of the branches. AuNSs exhibited excellent enhancement of surface-enhanced Raman scattering (SERS) intensities as the result of high electron density localized at the tips; however, the enhancement degree varied in accordance with the size of branches. In addition, AuNSs showed high catalytic performance toward the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). Efficient catalysis over AuNSs originates from their corners, stepped surfaces and high electron density at the tips.

Identification of A Novel Small-Molecule Binding Site of the Fat Mass and Obesity Associated Protein (FTO).

N-(5-Chloro-2,4-dihydroxyphenyl)-1-phenylcyclobutanecarboxamide (N-CDPCB, 1a) is found to be an inhibitor of the fat mass and obesity associated protein (FTO). The crystal structure of human FTO with 1a reveals a novel binding site for the FTO inhibitor and defines the molecular basis for recognition by FTO of the inhibitor. The identification of the new binding site offers new opportunities for further development of selective and potent inhibitors of FTO, which is expected to provide information concerning novel therapeutic targets for treatment of obesity or obesity-associated diseases.