Ring Substitution Research Articles

Ultra-fast UPLC–MS/MS approach for estimating X-376 in human liver microsomes: Evaluation of metabolic stability via in silico software and in vitro analysis

X-376 is a novel anaplastic lymphoma kinase (ALK) inhibitor that is capable of penetrating the blood brain barrier. This makes it suitable for use in patients with ALK-positive non-small cell lung cancer (NSCLC) who have metastases in the central nervous system. This study developed a highly sensitive, fast, eco-friendly, and reliable UPLC-MS/MS approach to quantify X-376 in human liver microsomes (HLMs). This approach was used to evaluate X-376's metabolic stability in HLMs in vitro. The UPLC-MS/MS analytical technique validation followed US-FDA bio-analytical method validation guidelines. StarDrop software, containing P450 metabolic and DEREK modules, was utilized to scan X-376's chemical structure for metabolic lability and hazardous warnings. X-376 and Encorafenib (ENF as internal standard) were resoluted on the Eclipse Plus C18 column utilizing an isocratic mobile phase method. The X-376 calibration curve was linear from 1 to 3000 ng/mL. The precision and accuracy of this study's UPLC-MS/MS approach were tested for intra- and inter-day measurements. Inter-day accuracy was −1.32% to 9.36% while intra-day accuracy was −1.5% to 10.00%. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of X-376 were 59.77 mL/min/kg and 13.56 min. The high extraction ratio of X-376 supports the 50 mg twice-daily dose for ALK-positive NSCLC and CNS metastases patients. In silico software suggests that simple structural changes to the piperazine ring or group substitution in drug design may improve metabolic stability and safety compared to X-376.

Synthesis and anticancer properties of novel dolastatin 10 analogs featuring five-membered heterocyclic rings with a linkable group at the C-terminus

Dolastatin 10 (Dol-10), a natural marine-source pentapeptide, is a powerful antimitotic agent regarded as one of the most potent anticancer compounds found to date. Dol-10 however, lacks chemical conjugation capabilities, which restricts the feasibility of its application in targeted drug therapy. This limitation has spurred the prospect that chemical structure of the parent molecule might allow conjugation of the derivatives to drug carriers such as antibodies. By first employing docking studies, we designed and prepared a series of novel Dol-10 analogs with a modified C-terminus, preserving high potency of the parent compound while enhancing conjugation capability. The modifications involved the introduction of a methyleneamine functionality at position 4 of the 1,3-thiazole ring, along with the substitution of the thiazole ring with a 1,2,3-triazole moiety, furnished with methylenehydroxy, carboxy, methyleneamine, and N(Me)-methyleneamine tethering functionalities at position 4. Among the synthesized pentapeptides, DA-1 exhibited the highest potency in prostate cancer (PC-3) cells, eliciting apoptosis (IC50 0.2 ± 0.1 nm) and cell cycle arrest at the mitotic stage after at least 6 days of culture. This delayed response suggests the accumulation of cellular stress or significant physiological alterations that profoundly impact the cell cycle. We believe that these novel Dol-10 derivates represent a new and straightforward route for the development of C-terminus modified Dol-10-based microtubule inhibitors, thereby advancing targeted anticancer therapy.

Facile Synthesis and Applications of Flavonoid-Heterocyclic Derivatives

Abstract: Flavonoids belong to the polyphenol group that naturally exists in fruits, vegetables, tea, and grains. Flavonoids, as secondary metabolites, show indispensable contributions to biolog-ical processes and the responses of plants to numerous environmental factors. The bioactivity of flavonoids depends on C6-C3-C6 ring substitution patterns that exhibit bioactive antioxidant, an-timicrobial, antifungal, antitumor, and anti-inflammatory properties. The synthesis of flavonoids has been reported by various methodologies. Therefore, the present review systematically sum-marizes the synthesis of recent heterocyclic flavonoid derivatives via facile synthetic approaches since the research in flavonoids is useful for therapeutic and biotechnology fields.

Discovery of Novel Pyridazine Herbicides Targeting Phytoene Desaturase with Scaffold Hopping.

Phytoene desaturase (PDS) is a critical functional enzyme in blocking ζ-carotene biosynthesis and is one of the bleaching herbicide targets. At present, norflurazon (NRF) is the only commercial pyridazine herbicide targeting PDS. Therefore, developing new and diverse pyridazine herbicides targeting PDS is urgently required. In this study, diflufenican (BF) was used as the lead compound, and a scaffold-hopping strategy was employed to design and synthesize some pyridazine derivatives based on the action mode of BF and PDS. The preemergence herbicidal activity tests revealed that compound 6-chloro-N-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenoxy)pyridazine-4-carboxamide (B1) with 2,4-diF substitution in the benzeneamino ring showed 100% inhibition rates against the roots and stems of Echinochloa crus-galli and Portulaca oleracea at 100 μg/mL, superior to the inhibition rates of BF. Meanwhile, compound B1 demonstrated excellent postemergence herbicidal activity against broadleaf weeds, which was similar to that of BF (inhibition rate of 100%) but superior to that of NRF. This indicated that 6-Cl in the pyridazine ring is the key group for postemergence herbicidal activity. In addition, compound B1 could induce downregulation of PDS gene expression, 15-cis-phytoene accumulation, and Y(II) deficiency and prevent photosynthesis. Therefore, B1 can be considered as a promising candidate for developing high-efficiency PDS inhibitors.

Theoretical screening of N-[5'-methyl-3'-isoxasolyl]-N-[(E)-1-(-2-thiophene)] methylidene]amine and its isoxazole based derivatives as donor materials for bulk heterojunction organic solar cells: DFT and TD-DFT investigation.

In the present work, the influence of aromatic ring substitution on a series of small-donor organic molecules (A, B, C, D, and E) with isoxazole cores was investigated for photovoltaic applications in organic solar cells. Frontier molecular orbital analysis, chemical reactivity descriptors, dipole moment, and population analysis showed that all the organic materials have intramolecular charge transfer abilities capable of donating electrons to the acceptor material (PCBM). The required photovoltaic parameters such as Voc, FF, Jsc, LHE, and other associated optoelectronic parameters are reported. The results demonstrate that aromatic ring substitution influences charge transfer and power conversion efficiencies of solar cells. That is, an increase in the aromatic character of a material increases its charge transfer, and as a result, its photovoltaic properties are increased. Additionally, all the investigated derivatives are good charge transporters with suitable electron reorganization energies, which are beneficial for minimizing energy loss. Hence, these organic derivatives with isoxazole backbones are promising materials and may provide fresh insights into the design of new materials for organic solar cell applications. All calculations were performed using DFT and the ORCA 4.1.0 program package as the main tool for geometry optimization and frequency calculations. The Avogadro 1.2.1 visualization tool was used to prepare all input files executed by ORCA 4.1.0. The BP86, B3LYP, and wB97M series of functionals coupled with the def2/TZVP basis set were employed for geometry optimization. All energy-related calculations were carried out using the M06-2x functional. Multiwfn version 3.7 was used for aromaticity and population analysis. Excited state and UV-visible spectra were simulated using the TD-DFT method at the CAM-B3LYP-D3, wB97X-D3, and PBE0-D3 coupled with the ma-def2-TZVP basis set. Moreover, solvent effects were incorporated using the SMD scheme as incorporated in the ORCA software. Lastly, the RIJCOSX approximations were used to speed up calculations while maintaining accuracy.

Antiproliferative and Pro-Apoptotic Activity and Tubulin Dynamics Modulation of 1H-Benzimidazol-2-yl Hydrazones in Human Breast Cancer Cell Line MDA-MB-231.

(1) Background: The aim of the work is the evaluation of in vitro antiproliferative and pro-apoptotic activity of four benzimidazole derivatives containing colchicine-like and catechol-like moieties with methyl group substitution in the benzimidazole ring against highly invasive breast cancer cell line MDA-MB-231 and their related impairment of tubulin dynamics. (2) Methods: The antiproliferative activity was assessed with the MTT assay. Alterations in tubulin polymerization were evaluated with an in vitro tubulin polymerization assay and a docking analysis. (3) Results: All derivatives showed time-dependent cytotoxicity with IC50 varying from 40 to 60 μM after 48 h and between 13 and 20 μM after 72 h. Immunofluorescent and DAPI staining revealed the pro-apoptotic potential of benzimidazole derivatives and their effect on tubulin dynamics in living cells. Compound 5d prevented tubulin aggregation and blocked mitosis, highlighting the importance of the methyl group and the colchicine-like fragment. (4) Conclusions: The benzimidazole derivatives demonstrated moderate cytotoxicity towards MDA-MB-231 by retarding the initial phase of tubulin polymerization. The derivative 5d containing a colchicine-like moiety and methyl group substitution in the benzimidazole ring showed potential as an antiproliferative agent and microtubule destabilizer by facilitating faster microtubule aggregation and disrupting cellular and nuclear integrity.

Differentiation of regioisomeric N-substituted meta-chlorophenylpiperazine derivatives

A series ofN,N-disubstituted piperazines were synthesized containing the structural elements of meta-chlorophenylpiperazine (mCPP) in combination with methoxybenzyl-, and dimethoxybenzyl substituents to yield nineN,N-disubstituted piperazine compounds. These nine potential designer-like drug analogs were prepared based on common designer trends and regioisomeric differentiation was based on gas chromatography-mass spectrometry (GC–MS) and gas chromatography-vapor phase infrared (GC–vpIR) studies.The compounds in this study have not been reported as drugs of abuse at this time. However, commercial availability of precursor chemicals including mCPP suggests the possibility of further designer exploration. Capillary GC separation showed the regioisomers to elute according to the position of aromatic ring substitution and/or the degree of substituent crowding on the aromatic ring. Numerous electron ionization (EI) mass spectral fragment ions occur via processes initiated by one of the two nitrogen atoms of the piperazine ring. The major EI-MS fragment ions observed in all nine spectra occur at m/z 195 from the loss of the substituted benzyl radical and the cation atm/z56 (C3H6N)+from the piperazine ring. Unique radical cations at m/z 136 and m/z 152 are characteristic of the 2,3- and 3,5-dimethoxybenzyl isomers, respectively. The vapor phase infrared spectra for all nine compounds show a strong absorption band in the 1591–1593 cm−1region indicative of the chloroaniline moiety. Numerous bands in the 1600–650 cm−1region provide data for the differentiation of the methoxy and dimethoxybenzyl ring substitution patterns. Thus, a combination of EI-MS and vapor phase IR allow for the differentiation and specific identification of each regioisomer in this study.

CPD model prediction of oil sand pyrolysis based on structural parameters from 13C NMR and FTIR measurements

Here, carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) and Fourier transform infrared spectroscopy (FTIR) techniques were used to study the chemical structure characteristics of oil sand and its pyrolysis oil. The FTIR results showed that the values of the CH2/CH3 ratio, A-factor, and DOC1 of the pyrolysis oil decreased during the pyrolysis process, while the C-factor showed a maximum value with increasing pyrolysis temperature. The 13C NMR results showed that methylides and methylides were mainly contributed to oil production. The aliphatic chain in the pyrolysis oil has little alterations during pyrolysis, while the extent of aromatic ring substitution increases from 0.46 to 0.58. Furthermore, a correlation was obtained between the chemical structure of oil and the pyrolysis product yields of oil sand. Moreover, using chemical structure parameters investigated with FTIR and 13C NMR and kinetic parameters based on the thermogravimetric data, the chemical percolation devolatilization (CPD) model was applied to simulate the pyrolysis of oil sand. The results showed that the simulated results for tar and light gas were in good agreement with the experimental data, while those for char underpredicted the experimental data. Overall, the CPD model can effectively predict the pyrolysis of oil sand.

Combined computational and synthetic strategies for the development of potent pyrazolo-pyridine derivatives as anticancer agents

PI3K comprise a group of lipid kinases mainly made up of three classes and have a particular role in signal transduction. The aberration of class IA PI3K is most frequently shown in cancer. The computation techniques have been applied for the identification of potent compounds. This involved the generation of a library of novel compounds (2700) through R-group enumeration study. The screening process utilized a combination of pharmacophore-based virtual screening and various docking algorithms, leading to the discovery of ten novel compounds. The docking studies against PI3K kinase highlighted MSA6 and MSA7 as the most promising compounds, with docking scores of -9.03 and -9.0 kcal/mol, respectively. Results of docking studies of all derivatives confirmed satisfactory binding mode of the compounds within the active site of the target protein PI3K kinase. The screened pyrazolo-pyridine derivatives (MSA1-MSA10) were synthesized and evaluated as anti-cancer agents against NSCLC using A549 cell line. MSA6 showed the dose dependent enhancement in ROS production at concentration of 10 and 20 µM in A549 cells. MSA6 triggered caspase 3 cleavage in lung cancer cells in a dose-dependent manner. MSA6 treatment at 10 and 20 µM levels boosted NF-κβ expression in the cytoplasm while decreasing it in the nucleus, as demonstrated by flow cytometry with an anti-NF-κβ antibody. The modulation of PI3K activity have been observed at 10 µM and 20 µM concentration of MSA6. A549 cells treated with MSA6 with 20 µM showed significant reduction in wound healing in cancerous cell. A549 cells treated with 20 µM showed significantly reduction in number of colonies compared to control group. Compound MSA6 having a methyl group at the para position of phenyl ring at imine carbon and phenyl ring substitution at nitrogen of pyrazole ring exhibited remarkable growth inhibitory activity with IC50 value of 49.23 μM. Based on the above results, pyrazolo-pyridine derivatives can be used for the further development of novel PI3K kinase inhibitors as anticancer agents.

Efficient removal of Basic Violet 16 by a multistage oxygen enhanced liquid glow discharge plasma system: Mechanism and roles of reactive species quantified by machine learning

A multistage oxygen enhanced Liquid Glow Discharge Plasma reactor (LGDP/multistage oxygen, LGDP/M-O2) was designed to improve the removal efficiency of organic dyes in wastewater. As a result of the multistage oxygen system, the degradation rate constant of Basic Violet 16 (BV16) was enhanced by approximately 18 times, the decolorization rate of BV16 was 97.39 % in 4 min, and the removal rate of TOC was 33.32 % in 10 min. Detailed study of how the system works to help break down pollutants. The reactive species series of experiments showed that multistage oxygen injection strongly promoted reactive species production and utilization. Meanwhile, a machine learning model to quantify the contribution of reactants was proposed. Machine learning indicated the dominating contribution of reactive oxygen species (63.89 %) and reactive chlorine species (21.92 %) in the degradation of BV16. In addition, the transformation intermediates during the degradation of BV16 were monitored. Accordingly, three possible degradation pathways of BV16 in the LGDP/M-O2 system were proposed, i.e., benzene ring substitution of hydroxyl groups, hydroxyl addition of C=C double bond, and halogenation of benzene rings. This study demonstrates the importance of the LGDP/M-O2 system for organic dye removal from wastewater.

Effect of ionic liquid-surfactant compound solutions on the wettability and functional groups of coal

In order to investigate the feasibility of ionic liquid-surfactant compound solutions for coal dust suppression, three ionic liquids and sodium alpha-olefin sulfonate (AOS) were selected to be compounded respectively. The compound solutions were optimized by surface tension tests and coal dust settling experiments, and FTIR and SEM tests were carried out on coal samples treated with the optimum wetting agent. The results show that when the concentration is 0.3 wt%, and the ratio of [Bmim][Cl]/AOS is 4:6, the wetting rate of compound solution is the maximum. The content of hydrophilic functional groups OH…O and C-O in the coal samples increases significantly, and the degree of benzene ring substitutions is elevated; while hydrophobic functional groups –CH, aromatic ring C = C, and benzene ring 3 substitutions (3H) are destroyed by dissolution. The micromorphology of the coal surface changes with the appearance of many cracks and pores and an increase in surface roughness. [Bmim]+ can adsorb on the drain absorption points on the coal surface by electrostatic effect, turning them into water absorption sites and attracting the surrounding AOS molecules to arrange the composite adsorption layer more closely. These results can contribute to the development of novel wetting agents with specific structures and provide theoretical guidance for the reduction of coal dust concentrations.

New thiazole derivatives: Synthesis, X-ray crystal structure, Hirshfeld surface analysis, and biological evaluations as potential antimicrobial and antitumor agents

Thiazole ring has a wide range of biological activities which is proven by its presence in more than eighteen FDA-approved drugs in addition to several compounds that are currently under clinical investigation. Substitution of the thiazole ring at positions 2,4, and 5 led to new derivatives with potent biological activities. Interestingly, the bromination of ethyl 2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)acetate (1) in acetic acid afforded (Z)-ethyl 2-(5‑bromo-4-(bromomethyl)-3-phenylthiazol-2(3H)-ylidene)-2-cyanoacetate (2) instead of the expected bromomethyl derivative 3. The reaction of thiazole derivative 2 with p-anisidine or aniline produced the corresponding thiazole derivatives 5a,b. The synthesized compounds were characterized based on their spectral and elemental data. Moreover, the structure of compound 2 was determined through X-ray crystallography. The molecular structure of 2 was crystallized in the orthorhombic, Pna21, a = 15.8144 (6) Å, b= 9.0238 (4) Å, c = 11.3296 (4) Å, V = 1616.80 (11) Å3, Z = 4. Analysis of the dnorm map and fingerprint plot for all possible intermolecular interactions in the crystal structure of thiazole 2 indicated the importance of the Br…O, O…H, and Br…H interactions in the molecular packing. The O1…H14A (2.548 Å), Br1…O1 (3.211 Å) and Br2…H7B (2.931 Å) interactions are the most short contacts. In addition, the percentages of the Br…O, O…H, and Br…H contacts are 2.3, 10.3 and 22.1 %, respectively. The antimicrobial activity of thiazole derivative 5a was tested, and the results revealed that it is equipotent to both Ampicillin against Staphylococcus aureus and to Gentamycin against Salmonella SP. In comparison to Doxorubicin, thiazole 5a showed less antitumor activity against the hepatocellular carcinoma (HepG-2) and colon carcinoma (HCT-116) cell lines.

CARBOXYLATION OF HYDROXYARENES WITH POTASSIUM SALTS OF ALKYLCARBONIC ACID

In this article it was demonstrated that potassium ethyl carbonate can be successfully utilized within the phenol and its derivatives carboxylation. The optimal reaction conditions for m-cresol were determined: substrate to potassium ethyl carbonate ratio 2:1, temperature 180°C, pressure 10 atmospheres and reaction time 6 hours. Importantly, the carboxylation of m-cresol is selective and resulted in the obtaining of 4-methyl-2-hydroxybenzoic acid in 90% yield.To study the impact of the nature and location of substituents in the phenyl ring on the yield of the desired products, carboxylation reactions of various phenol derivatives were carried out with the use of potassium ethyl carbonate. As a result of the investigation, the optimal carboxylation reaction parameters for each of the phenol derivatives were determined.This study may have practical applications in the development of laboratory and manufacturing approaches for the synthesizing of valuable hydroxybenzoic acids and their derivatives. It was discovered that carboxylation of phenol derivatives by potassium ethyl carbonate occurs via electrophilic substitution of the aromatic ring. The most active in this reaction are p-cresol (84%), mcresol (90%), o-cresol (80%) and resorcinol (73%). It was observed that p-chlorophenol (18%), pbromophenol (48%) and p-fluorophenol (58%) showed less pronounced activity.

A Combination of Pharmacophore Generation, Ligand-based Virtual Screening, Atom-based 3D-QSAR, and Molecular Docking Studies on Febuxostat-based Amides Analogues as Anti-inflammatory Agents.

A defence mechanism of the body includes inflammation. It is a process through which the immune system identifies, rejects, and starts to repair foreign and damaging stimuli. In the world, chronic inflammatory disorders are the leading cause of death. To obtain optimized pharmacophore, previously reported febuxostat- based anti-inflammatory amide derivatives series were subjected to pharmacophore hypothesis, ligand-based virtual screening, and 3D-QSAR studies in the present work using Schrodinger suite 2022-4. QuikProp module of Schrodinger was used for ADMET prediction, and HTVS, SP, and XP protocols of GLIDE modules were used for molecular docking on target protein (PDB ID:3LN1). Utilising 29 compounds, a five-point model of common pharmacophore hypotheses was created, having pIC50 ranging between 5.34 and 4.871. The top pharmacophore hypothesis AHHRR_ 1 model consists of one hydrogen bond acceptor, two hydrophobic groups and two ring substitution features. The hypothesis model AHHRR_1 underwent ligand-based virtual screening using the molecules from Asinex. Additionally, a 3D-QSAR study based on individual atoms was performed to assess their contributions to model development. The top QSAR model was chosen based on the values of R2 (0.9531) and Q2 (0.9424). Finally, four potential hits were obtained by molecular docking based on virtual screening. The virtual screen compounds have shown similar docking interaction with amino acid residues as shown by standard diclofenac sodium drugs. Therefore, the findings in the present study can be explored in the development of potent anti-inflammatory agents.

Synthesis of urolithin derivatives and their anti-inflammatory activity

Two series of urolithin derivatives, totally 38 compounds, were synthesized. Their anti-inflammatory activity was investigated by detecting the inhibitory effects on the expression of TNF-α in bone marrow-derived macrophages (BMDMs), showing that 24 of 38 ones reduced the expression of TNF-α. Compound B2, the ring C opened derivative of urolithin B with a butoxycarbonyl substitution in ring A, showed the strongest inhibitory activity compared with that of indomethacin. Furthermore, B2 treatment decreased the expression of pro-inflammatory factors IL-1β, IL-6, iNOS and COX-2. Mechanically, the anti-inflammatory effect of B2 was related to the inhibition of NF-κB signaling pathway. These results clearly illustrated that B2 hold potential for application as an anti-inflammatory agent. The present study provided a viable approach to modify the gut metabolites for anti-inflammatory drug development.

Design, synthesis and in-vitro anti-depressant activity evaluation of some 2-styrylbenzimidazole derivatives

BackgroundExisting antidepressants possess various adverse effects and so they are not considered as the first line of drug in mild depression. The lack of proper drugs to treat the mild depression on the other hand alleviates severe depressive cases. To overcome this problem, the nucleus of benzimidazole and cinnamic acid having very less toxicity were fused and a small library of 40 compounds was prepared. The library was then screened for ADMET properties and probable toxicity. Those compounds which had not shown any toxicity as well as possessed better in-silico absorption, distribution and metabolism were selected for the first phase of the study. Synthesized compounds were characterized by FTIR, 1H-NMR and 13C-NMR and were screened for in-vitro antidepressant activity by DNPH spectrophotometry.ResultThe compounds MS-3 and MS-8 had shown good antidepressant activity with IC50 values of 367.19 μM/mL and 184.56 μM/mL against MAO-A and MAO-B, respectively.ConclusionFrom this study, it can be concluded that the structural requirements for the inhibition of MAO-A and MAO-B were totally different. MAO-A inhibitors required the presence of nitrogen and oxygen containing ring substitutions whereas MAO-B inhibitors required the presence of 4-halogen containing phenyl ring substitutions.Graphical abstract

Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations.

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity.

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4weeks of daily dermal administration.

ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.

Making and Breaking Helical Open-Chain Oligopyrroles.

Closed-chain oligopyrroles such as porphyrins or corroles have been well-established in literature and experience a steadily strong interest by several fields of science. However, their open-chain derivatives are comparatively underrepresented, despite their intriguing properties and promising applications. Here, we aim to review typical synthetic routes, as well as point towards several emergent properties, marking them as interesting candidates for various fields of study. The review focuses on two traditional methods (each starting from highly symmetric metalloporphyrins) and then expands its scope towards more recent variations before moving on to more exotic and recent highlights that have yet to be included into the canon. Key chemical reactivities (ring closure, substitution and fragmentation) are then followed by notable physicochemical properties, placing special emphasis on potential uses in molecular electronics and sensors.

Novel chemical tyrosine functionalization of adeno-associated virus improves gene transfer efficiency in liver and retina

Decades of biological and clinical research have led to important advances in recombinant adeno-associated viruses rAAV-based gene therapy gene therapy. However, several challenges must be overcome to fully exploit the potential of rAAV vectors. Innovative approaches to modify viral genome and capsid elements have been used to overcome issues such as unwanted immune responses and off-targeting. While often successful, genetic modification of capsids can drastically reduce vector yield and often fails to produce vectors with properties that translate across different animal species, such as rodents, non-human primates, and humans. Here, we describe a chemical bioconjugation strategy to modify tyrosine residues on AAV capsids using specific ligands, thereby circumventing the need to genetically engineer the capsid sequence. Aromatic electrophilic substitution of the phenol ring of tyrosine residues on AAV capsids improved the in vivo transduction efficiency of rAAV2 vectors in both liver and retinal targets. This tyrosine bioconjugation strategy represents an innovative technology for the engineering of rAAV vectors for human gene therapy.