Moderate Selectivity Research Articles

Processes of 1,3-Dipolar cycloaddition in nucleoside, nucleotide and bio conjugation and its importance in medicinal chemistry

In the 1,3-dipolar cycloaddition, a 1,3-dipole and a dipolarophile interact chemically to produce a five-membered ring. The Huisgen cycloaddition occurs when an organic azide and an alkyne unite to form a 1,3-dipolar cycloaddition that results in a 1,2,3-triazole. 1,3-dipolar cycloaddition is an essential step in the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives. Some of the cycloadducts produced by these reactions were converted into enantiopure precursors known to exist in some biologically active chemicals as well as an active stereoisomer of a pine sawfly sex pheromone. The synthesis of several new enantiopure organocatalysts that were shown to be helpful in some The synthetic utility of these 1,3-dipolar cycloaddition processes with nitrones and a,b-unsaturated aldehydes was further demonstrated. There are times when these reactions have modest to moderate diastereofacial selectivity. the choose actual and nonracemic have improved. Compound collections are created in chemical biology research using the BIOS concept, which draws its inspiration from natural product scaffolds. In BIOS, the primary criterion utilized to develop hypotheses for the design and synthesis of targeted chemical libraries is biological relevance. Because they outline the chemical domains that nature has explored, the underlying scaffolds of natural product classes in particular serve as an inspiration for BIOS because they can be thought of as "trivet can often be achieved if both the azomethine ylide and the dipolarophile are chi privileged

Efficient hydrostannation of fluorinated alkenes

Hydrostannation reactions of a variety of fluoroalkenes using HSnBu3 and UV irradiation have been developed. The reactions occur under mild conditions via a radical chain pathway in good yields and with moderate selectivity. In addition, the synthesis of tin derivatives of fluorinated alkenes was investigated in order to study their applicability for Stille type cross-coupling reactions.

High-Temperature Conversion of Olefins to Liquid Hydrocarbons on γ-Al2O3

Noncatalytic thermal conversion of light olefins proceeds at industrially relevant rates at temperatures above 450 °C and pressures above 50 bar. The discovery of solid acid oligomerization catalysts permitted the use of milder conditions (<300 °C) and significantly improved the octane rating. However, Brønsted acid catalysts deactivate and must be regenerated frequently. In this study, at reaction temperatures of about 250–450 °C and pressures of 1 to 40 bar, olefins react on γ-alumina to form higher molecular weight products. The rate of propylene is about ten times higher than that of ethylene. The products, however, are not a simple olefin oligomerization distribution, and many nonoligomer products are formed. The primary products undergo secondary reactions, including double bond isomerization and H-transfer, giving moderate selectivities for saturated products. Depending on the conversion, temperature, and pressure, the rate of ethylene conversion on alumina is more than 100 times that of thermal, noncatalytic conversion. The apparent activation energy for ethylene conversion is 55–75 kJ/mol, which is much lower than ∼244 kJ/mol observed for the thermal gas-phase reaction. On alumina, some reactants and products undergo disproportionation reactions. For example, propylene forms equal molar amounts of ethylene and iso-butene even at very low conversions. Lewis acid sites on γ-alumina have previously been proposed as the active site for double bond isomerization and H–D exchange. Thus, it seems likely that Lewis acid sites are also catalytic for olefin oligomerization and disproportionation reactions. With the γ-alumina catalyst, high liquid yields can be achieved with little formation of coke and minimal deactivation for at least several days.

Lines of descent in a Moran model with frequency-dependent selection and mutation

We study ancestral structures for the two-type Moran model with mutation and frequency-dependent selection under the nonlinear dominance or fittest-type-wins scheme. Under appropriate conditions, both lead, in distribution, to the same type-frequency process. Reasoning through the mutations on the ancestral selection graph (ASG), we develop the corresponding killed and pruned lookdown ASGs and use them to determine the present and ancestral type distributions. To this end, we establish factorial moment dualities to the Moran model and a relative. We extend the results to the diffusion limit and present applications for finite populations, as well as for moderate and weak selection limits.

Monoterpenoid 5-methylcoumarins from Centrapalus pauciflorus with antiproliferative activity

Thirteen undescribed monoterpene-fused 5-methylcoumarins, named centrapalus coumarins A–M, were isolated from the aerial parts of the Centrapalus pauciflorus together with seven known compounds. The structures were established by extensive spectroscopic analyses, including 1D NMR, 2D NMR, and HR-ESI-MS experiments. The compounds represent a wide range of chemical diversity depending on the connection of the head-to-tail coupled diisoprene unit. Centrapalus coumarins A–H and I–L are based on 6–6–6- and 6–6-7-membered tricyclic ring systems, respectively. Centrapalus coumarins D and E exhibit cyclic hemiketal structures, while centrapalus coumarins F is unique because its monoterpene part forms an additional lactone ring. Centrapalus coumarin L is the only compound containing a modified trinor-monoterpene part. Centrapalus coumarin M is unprecedented as it contains a pentacyclic heterocyclic ring system. Sixteen isolated compounds were investigated for antiproliferative activity on the human breast (MCF-7 and MDA-MB-231), cervical (HeLa and SiHa), and ovarian (A2780) cancer-cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and a few of them exhibited substantial activity. Centrapalus coumarin F demonstrated the highest potency against MCF-7, HeLa, and A2780 cells with IC50 values of 6.59, 2.28, and 15.41 μM, respectively. The cytotoxic activity of centrapalus coumarin F showed moderate cancer selectivity, as determined using intact fibroblast cells (NIH-3 T3). The antiproliferative activity of these 5-methylcoumarin derivatives provides evidence for the establishment of structure–activity relationships.

Predicting Highly Enantioselective Catalysts Using Tunable Fragment Descriptors.

Catalyst optimization processes typically rely on inductive and qualitative assumptions of chemists based on screening data. While machine learning models using molecular properties or calculated 3D structures enable quantitative data evaluation, costly quantum chemical calculations are often required. In contrast, readily available binary fingerprint descriptors are time- and cost-efficient, but their predictive performance remains insufficient. Here, we describe a machine learning model based on fragment descriptors, which are fine-tuned for asymmetric catalysis and represent cyclic or polyaromatic hydrocarbons, enabling robust and efficient virtual screening. Using training data with only moderate selectivities, we designed theoretically and validated experimentally new catalysts showing higher selectivities in a challenging asymmetric tetrahydropyran synthesis.

Predicting Highly Enantioselective Catalysts Using Tunable Fragment Descriptors**

AbstractCatalyst optimization processes typically rely on inductive and qualitative assumptions of chemists based on screening data. While machine learning models using molecular properties or calculated 3D structures enable quantitative data evaluation, costly quantum chemical calculations are often required. In contrast, readily available binary fingerprint descriptors are time‐ and cost‐efficient, but their predictive performance remains insufficient. Here, we describe a machine learning model based on fragment descriptors, which are fine‐tuned for asymmetric catalysis and represent cyclic or polyaromatic hydrocarbons, enabling robust and efficient virtual screening. Using training data with only moderate selectivities, we designed theoretically and validated experimentally new catalysts showing higher selectivities in a challenging asymmetric tetrahydropyran synthesis.

Stepwise photoassisted decomposition of carbohydrates to H2

Stepwise photoassisted decomposition of carbohydrates to H2

Dopamine D3/D2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

Room-Temperature Sub-ppm Detection and Machine Learning-Based High-Accuracy Selective Analysis of Ammonia Gas Using Silicon Vertical Microwire Arrays

The potential applications of silicon microwire materials in monitoring gases have not been fully exploited. Uniform silicon vertical microwire arrays (Si VMWA) are fabricated using a metal-assisted chemical etching process after optimizing the conditions. The characteristics and responses of Si VMWA-based sensors with different diameters to ammonia gas (NH3) are investigated in both air and nitrogen environments. The sensing mechanism of the sensor to NH3 is discussed to clarify the response in different environments. The sensor exhibits a linear response to a wide range of NH3 concentrations (4%@2 ppm–122%@500 ppm) at room temperature and even shows a distinct response at 200 ppb of NH3. In addition, it demonstrates great repeatability/reversibility and moderate selectivity to ammonia gas against other gases (nitrogen dioxide, toluene, and isobutane). Furthermore, machine learning-based principal component analysis and random forest algorithms enable us to discriminate NH3 from other possible interfering gases and predict gas concentration with an accuracy of over 95%. Thus, our approach using the Si VMWA-based sensor with machine learning-based data analysis represents a significant step toward the environmental sensing of specific chemical analytes in the household and industries.

ALKYLATION OF PHENOL WITH METHANOL BY USING ZEOLITE CATALYSTS

Alkylation of phenol with methanol using beta zeolite, H-beta zeolite, MCM-22, and H-MCM-22 was studied on a continuous fixed bed reactor. The obtained products were anisole, o-cresol, p-cresol, and 2,4-xylenol. The effect of various parameters such as mole ratio of reactants (phenol:methanol), temperature, and time on stream were studied to attain the highest phenol conversion and the selectivity of the individual products. The maximum conversion of phenol was exhibited by H-MCM-22 with moderate anisole selectivity of 21&amp;#37;. The best selectivity of anisole (63&amp;#37;) was obtained by H-beta zeolite with 50&amp;#37; conversion of phenol. Selectivity of anisole decreases with increase in temperature which suggests that at high temperature C-methylation is favored over O-methylation. In addition, selectivity of anisole increases with the increase of the phenol to methanol feed ratio. The time on stream shows an increase in selectivity of anisole, p-cresol, and o-cresol with a decrease in 2,4-xylenol selectivity.

A Gemini basic ionic liquid and functionalized cellulose nanocrystal-based mixed matrix membrane for CO2/N2 separation.

Owing to the adverse environmental impact, carbon capture and separation have gained tremendous interest throughout the globe. Herein, a CO2/N2 gas separative mixed matrix membrane containing amine functionalized cellulose nanocrystals and a Gemini basic ionic liquid has been developed, which exhibits the highest permeance of 21 033 GPU and moderate selectivity of 21.3.

Metal–Organic Cage Extended Amorphous Network via Anionic Organic Linkers for Cr2O72– and Iodine Adsorption on Nanopores

The covalent linking of metal–organic cages (MOCs) with a nanoscale cavity is an efficient strategy to construct functional materials with different properties compared with bulk MOCs, but studies based on this topic are still less explored. In addition, toxic chemical and pollutant uptake, especially iodine vapor adsorption on MOC-based materials, still lacks investigation. Herein, an MOC-extended amorphous network (denoted MOC–DASD) via the covalent linking of an aldehyde-functionalized cationic Pd12L24 MOC (with about 3.5 nm in diameter) with an anionic organic linker, 4,4′-diamino-2,2′-stilbenedisulfonic acid (DASD), was constructed and applied to absorb Cr2O72– in water and capture I2 molecules in vapor. The covalent linkage of MOC and DASD via C═N bonds was confirmed by IR, Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and ζ-potential tests. In addition, the original NO3– anions can be easily removed from the MOC–DASD due to the introduction of an anionic linker, thus releasing more effective cavities for guest adsorption. Although there is a lack of exchangeable anions, MOC–DASD still exhibits the ability to capture Cr2O72– in water with moderate capacity and high selectivity. In addition, the MOC–DASD showed a significantly enhanced iodine vapor uptake capacity. The iodine uptake capacity of MOC–DASD reached 3.67 g/g, which is 1.8 times higher than that of bulk MOC. A mechanistic study shows that some of the iodine was closely adsorbed by charge transfer. The release of iodine at 120 °C reveals that approximately 74% of the absorbed iodine can be removed, and the MOC can uptake the iodine again with a capacity of 1.5 g/g, showing good reusability.

Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders

Targeting bromodomain-containing protein 9 (BRD9) represents a promising strategy for the development of new agents endowed with anticancer properties. With this aim, a set of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based compounds was investigated following a combined approach that relied on in silico studies, chemical synthesis, biophysical and biological evaluation of the most promising items. The protocol was initially based on molecular docking experiments, accounting a library of 1896 potentially synthesizable items tested in silico against the bromodomain of BRD9. A first set of 21 compounds (1–21) was selected and the binding on BDR9 was assessed through AlphaScreen assays. The obtained results disclosed compounds 17 and 20 able to bind BRD9 in the submicromolar range (IC50 = 0.35 ± 0.18 μM and IC50 = 0.14 ± 0.03 μM, respectively) showing a promising selectivity profile when tested against further nine bromodomains. Taking advantage of 3D structure-based pharmacophore models, additional 10 derivatives were selected in silico for the synthetic step and binding assessment, highlighting seven compounds (22, 23, 25, 26, 28, 29, 31) able to selectively bind BRD9 among different bromodomains. The ability of the identified BRD9 binders to cross artificial membranes in vitro was also assessed, revealing a very good passive permeability profile. Preliminary studies were carried out on a panel of healthy and cancer human cell lines to explore the biological behavior of the selected compounds, disclosing a moderate activity and significant selectivity profile towards leukaemia cells.These results highlighted the applicability of the reported multidisciplinary approach for accelerating the selection of promising items and for driving the chemical synthesis of novel selective BRD9 binders. Moreover, the low molecular weight of the reported 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based BRD9 binders suggests the possibility for further exploring the chemical space in order to obtain new analogues with improved potency.

Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity

Histone deacetylase 6 (HDAC6) is an attractive drug development target because of its role in the immune response, neuropathy, and cancer. Knockout mice develop normally and have no apparent phenotype, suggesting that selective inhibitors should have an excellent therapeutic window. Unfortunately, current HDAC6 inhibitors have only moderate selectivity and may inhibit other HDAC subtypes at high concentrations, potentially leading to side effects. Recently, substituted oxadiazoles have attracted attention as a promising novel HDAC inhibitor chemotype, but their mechanism of action is unknown. Here, we show that compounds containing a difluoromethyl-1,3,4-oxadiazole (DFMO) moiety are potent and single-digit nanomolar inhibitors with an unprecedented greater than 104-fold selectivity for HDAC6 over all other HDAC subtypes. By combining kinetics, X-ray crystallography, and mass spectrometry, we found that DFMO derivatives are slow-binding substrate analogs of HDAC6 that undergo an enzyme-catalyzed ring opening reaction, forming a tight and long-lived enzyme-inhibitor complex. The elucidation of the mechanism of action of DFMO derivatives paves the way for the rational design of highly selective inhibitors of HDAC6 and possibly of other HDAC subtypes as well with potentially important therapeutic implications.

Prioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection

Pathogen-driven selection shaped adaptive mutations in immunity genes, including those contributing to inflammatory disorders. Functional characterization of such adaptive variants can shed light on disease biology and past adaptations. This popular idea, however, was difficult to test due to challenges in pinpointing adaptive mutations in selection footprints. In this study, using a local-tree-based approach, we show that 28% of risk loci (153/535) in 21 inflammatory disorders bear footprints of moderate and weak selection, and part of them are population specific. Weak selection footprints allow partial fine-mapping, and we show that in 19% (29/153) of the risk loci under selection, candidate disease variants are hitchhikers, and only in 39% of cases they are likely selection targets. We predict function for a subset of these selected SNPs and highlight examples of antagonistic pleiotropy. We conclude by offering disease variants under selection that can be tested functionally using infectious agents and other stressors to decipher the poorly understood link between environmental stressors and genetic risk in inflammatory conditions.

Utilization of macrocyclic peptides to target protein-protein interactions in cancer.

Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.

Iron porphyrin with appended guanidyl group for significantly improved electrocatalytic carbon dioxide reduction activity and selectivity in aqueous solutions

AbstractIron porphyrins have high activity and selectivity for electrocatalytic CO2 reduction reaction (CO2RR) in nonaqueous solutions, but they usually display poor or moderate selectivity for CO2RR in aqueous solutions because of the competitive hydrogen evolution reaction. Using water as the electrocatalytic reaction solvent is more favored because not only it is cheap, green and abundant but also it can sufficiently provide protons required for CO2RR. Therefore, developing Fe porphyrins as electrocatalysts for efficient and selective CO2RR in aqueous solutions is of both fundamental and practical significance. Herein, we report the design and synthesis of Fe porphyrin 1 with an appended guanidyl group and its electrocatalytic features for CO2RR in both nonaqueous and aqueous solutions. In acetonitrile, Fe porphyrin 1 and its guanidyl-free analogue, tetrakis(3,4,5-trimethoxyphenyl)porphyrin 2, are both efficient for electrocatalytic CO2-to-CO conversion, but the turnover frequency with 1 (3.9 × 105 s−1) is one order of magnitude larger than that with 2 (1.7 × 104 s−1), showing the critical role of the appended guanidyl group in improving electrocatalytic CO2RR activity. More importantly, in 0.1 mol L−1 KHCO3 aqueous solutions, 1 showed very high selectivity for electrocatalytic CO2-to-CO conversion with a Faradaic efficiency of 96%, while 2 displayed a Faradaic efficiency of 65% for the CO2-to-CO conversion. This work is of significance to show the effect of appended guanidyl group on improving both activity and selectivity of Fe porphyrins for CO2RR electrocatalysis.

Evolution and codon usage bias of mitochondrial and nuclear genomes in Aspergillus section Flavi.

The fungal genus Aspergillus contains a diversity of species divided into taxonomic sections of closely related species. Section Flavi contains 33 species, many of industrial, agricultural, or medical relevance. Here, we analyze the mitochondrial genomes (mitogenomes) of 20 Flavi species-including 18 newly assembled mitogenomes-and compare their evolutionary history and codon usage bias patterns to their nuclear counterparts. Codon usage bias refers to variable frequencies of synonymous codons in coding DNA and is shaped by a balance of neutral processes and natural selection. All mitogenomes were circular DNA molecules with highly conserved gene content and order. As expected, genomic content, including GC content, and genome size differed greatly between mitochondrial and nuclear genomes. Phylogenetic analysis based on 14 concatenated mitochondrial genes predicted evolutionary relationships largely consistent with those predicted by a phylogeny constructed from 2,422 nuclear genes. Comparing similarities in interspecies patterns of codon usage bias between mitochondrial and nuclear genomes showed that species grouped differently by patterns of codon usage bias depending on whether analyses were performed using mitochondrial or nuclear relative synonymous usage values. We found that patterns of codon usage bias at gene level are more similar between mitogenomes of different species than the mitogenome and nuclear genome of the same species. Finally, we inferred that, although most genes-both nuclear and mitochondrial-deviated from the neutral expectation for codon usage, mitogenomes were not under translational selection while nuclear genomes were under moderate translational selection. These results contribute to the study of mitochondrial genome evolution in filamentous fungi.

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues.

With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin's promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a-c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a-c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs &gt; 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a &gt; 3b &gt; 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b &gt; 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a-c demonstrated significant binding affinity (-6.003 to -7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.