ChemRxiv
Not a member yet
27047 research outputs found
Sort by
Design & Synthesis of Novel Nitrofuranyl Indole Carboxylates as Potential Antibacterial Drug Conjugates
No full textMankind has immensely benefited from the first marketed antibacterial drug i.e. Salvarsan® in 1910 to the recently released Vaborem®, and the discovery of penicillin gave birth to the modern age of antibacterial treatment. Since the ‘golden age’ of antibacterial discovery (from the ‘40s to the ‘60s), in which most common antibacterial agents were discovered, antibacterial discovery has slowed dramatically with no new antibacterial scaffolds being introduced from 1962 until 2000. Recent developments in Oxford have led to identification of non-β-lactam indole carboxylates as potent metallo-β-lactamase inhibitors; as a result, and in extension of the aforementioned endeavours in combating antibacterial resistance, herein this work reports a set of novel nitrofuranyl indole carboxylates (NInCs) which are thought to have potential to be developed into antibacterial drug conjugates. Inasmuch as stable ester prodrugs of the aforementioned NInCs may be biologically inactive, this work also presents various methods for ester hydrolysis of these potential antibacterial drug conjugates together with some modification to their cleavable linkers
SHP-1 Variants Broaden the Understanding of pH-Dependent Activities in Protein Tyrosine Phosphatases
No full textThe protein tyrosine phosphatase (PTP) SHP-1 plays an important role in both immune regulation and oncogenesis. This enzyme is part of a broader family of PTPs that all play important regulatory roles in vivo. Common to these enzymes is a highly conserved aspartic acid (D421 in SHP-1) that acts as an acid/base catalysis during the PTP-catalyzed reaction. This residue is located on a mobile loop, the WPD-loop, the dynamical behavior of which is intimately connected to catalytic activity. The SHP-1 WPD-loop variants H422Q, E427A, and S418A have been kinetically characterized and compared to the WT enzyme. These variants exhibit limiting magnitudes of kcat ranging from 43% to 77% of the WT enzyme. However, their pH profiles are significantly broadened in the basic pH range. As a result, above pH 6 the E427A and S418A variants have notably higher turnover numbers than WT SHP-1. Molecular modeling results indicate that the shifted pH dependencies result primarily from changes in solvation and hydrogen-bonding networks that affect the pKa of the D421 residue, explaining the changes in pH-rate profiles for kcat on the basic side. In contrast, a previous study of a noncatalytic residue variant of the PTP YopH, which also exhibited changes in pH dependency, showed that catalytic change arose from mutation-induced changes in conformational equilibria of the WPD-loop. That finding, and the present study, show the existence of distinct strategies for nature to tune the activity of PTPs in particular environments through controlling the pH-dependency of catalysis
Novel machine learning approach toward classification model of HIV-1 integrase inhibitors
No full textHIV-1 (Human immunodeficiency virus-1) has been causing severe pandemics by attacking the immune system of its host. Left untreated, it can lead to AIDS (acquired immunodeficiency syndrome), where death is inevitable due to opportunistic diseases. Therefore, discovering new antiviral drugs against HIV-1 is crucial. This study aimed to explore a novel machine learning approach to classify compounds that inhibit HIV-1 integrase and screen the dataset of repurposing compounds. The present study had two main stages: selecting the best type of fingerprint or molecular descriptor using the Wilcoxon signed-rank test and building a computational model based on machine learning. In the first stage, we calculated 16 different types of fingerprint or molecular descriptors from the dataset and used each of them as input features for 10 machine-learning models, which were evaluated through cross-validation. Then, a meta-analysis was performed with the Wilcoxon signed-rank test to select the optimal fingerprint or molecular descriptor types. In the second stage, we constructed a model based on the optimal fingerprint or molecular descriptor type. This data followed the machine learning procedure, including data preprocessing, outlier handling, normalization, feature selection, model selection, external validation, and model optimization. In the end, an XGBoost model and RDK7 fingerprint were identified to be the most suitable. The model achieved promising results, with an average precision of 0.928 ± 0.027 and an F1-score of 0.848 ± 0.041 in cross-validation. The model achieved an average precision of 0.921 and an F1-score of 0.889 in external validation. Molecular docking was performed and validated by redocking for docking power and retrospective control for screening power, with the AUC metrics being 0.876 and the threshold being identified at –9.71 kcal/mol. Finally, 44 compounds from DrugBank repurposing data were selected from the QSAR model, then three candidates were identified as potential compounds from molecular docking, and PSI-697 was detected as the most promising molecule, with in vitro experiment being not performed (docking score: -17.14 kcal/mol, HIV integrase inhibitory probability: 69.81%
Organic semiconductor-BiVO4 tandems for solar-driven H2O and CO2 splitting
No full textPhotoelectrochemical (PEC) systems offer a promising platform towards direct solar light harvesting and chemical storage. However, most prototypes employ wide bandgap semiconductors, moisture-sensitive inorganic light absorbers, or corrosive electrolytes. Here, we introduce PEC devices based on an organic donor-acceptor bulk heterojunction (BHJ), which demonstrate long-term H2 evolution and CO2 reduction in benign aqueous media using a carbon-based encapsulant. Accordingly, PCE10:EH-IDTBR photocathodes display long-term H2 production for 300 h in a near-neutral pH solution, whereas photocathodes with a molecular CO2 reduction catalyst attain a CO:H2 selectivity of 5.41±0.53 under 0.1 sun irradiation. Their early onset potentials enable the assembly of PCE10:EH-IDTBR - BiVO4 artificial leaves, which couple unassisted syngas production with O2 evolution, sustaining a 1:1 ratio of CO to H2 over 96 h of operation
Development of a Sulfamate Tethered Aza-Michael Cyclization Allows for the Preparation of (-)-Negamycin tert-Butyl Ester
No full textWe present the first examples of intramolecular aza-Michael cyclizations of sulfamates and sulfamides onto pendant
α,β-unsaturated esters, thioesters, amides, and nitriles. Stirring substrate with catalytic quantities of the appropriate base delivers product in good yield and excellent diastereoselectivity. The reactions are operationally simple, can be performed open to air, and are tolerant of a variety of important functional groups. We highlight the utility of this technology by using it in the preparation of a (-)-negamycin derivative
Recent advances and biophysical applications of atomic force microscopy in cancer research: An overview
No full textThe implementation of atomic force microscopy (AFM) in cancer detection investigations has been made possible by new developments. Living cells\u27 physical and chemical characteristics fluctuate anytime their physiological environments are modified. Consequently, such physical and chemical traits may represent intricate biological functions happening within cells. The shape, flexibility, and adhesive characteristics of cells can alter while they are going through the tumorigenesis phase and are driven by environmental factors. In settings that are close to physiological, AFM can carry out surface mapping and ultrastructural characterization of live cells with atomic-level resolution, as well as capturing force spectroscopy data that enables the investigation of the mechanical characteristics of cells. As a result, high resolution studies concerning the structure and mechanical attributes of cancer cells may benefit from the application of AFM. The principles of operation theory, mode of operation, and technical characteristics of AFM are presented in this paper, along with its various applications and future possibilities in cancer studies
Organocatalytic hydration of activated alkynes
No full textHydration reactions consist of the introduction of a molecule of water into a chemical compound. This process is a particularly useful method to allow, for instance, the conversion of alkynes into carbonyls, which are strategic intermediates in the synthesis of a plethora of compounds. Herein we demonstrate that L-cysteine can catalyse the hydration of activated alkynes in a very effective and fully regioselective manner to access β-ketosulfones, amides and esters in aqueous conditions. The mild reaction conditions facilitated the integration with enzyme catalysis to access chiral β-hydroxy sulfones from the corresponding alkynes in a one-pot cascade process in good yields and excellent enantiomeric excess. These findings pave the way towards establishing a general method for metal-free, cost-effective, and more sustainable alkyne hydration processe
Approaching the Complete Basis Set Limit for Transition Metal Spin–State Energetics
No full textConvergence to the complete basis set (CBS) limit is analyzed for the problem of transition metal (TM) spin-state energetics by taking under scrutiny a benchmark set of 18 energy differences between spin states for 13 chemically diverse TM complexes. The performance of conventional CCSD(T) and explicitly correlated CCSD(T)-F12a/b calculations in approaching the CCSD(T)/CBS limits is systematically studied. An economic computational protocol is developed based on the CCSD-F12a approximation and (here proposed) modified scaling of the perturbative triples term, (T#). This computational protocol recovers relative spin–state energetics of the benchmark set in excellent agreement with the reference CCSD(T)/CBS limits (mean absolute deviation 0.4, mean signed deviation 0.2, and maximum deviation 0.8 kcal/mol) and enables performing canonical CCSD(T) calculations for mononuclear TM complexes sized up to ca. 50 atoms, which is illustrated by application to heme-related metalloporphyrins. Furthermore, a good transferability of the basis set incompleteness error (BSIE) is demonstrated for spin–state energetics calculated using CCSD(T) and other wave-function methods (MP2, CASPT2, CASPT2/CC, NEVPT2, MRCI+Q), which justifies efficient focal-point approximations and simplifies construction of multi-method benchmark studies
Unveiling the Mechanistic Role of Chiral Palladacycles in Pd(II)-Catalyzed Enantioselective C(sp3)-H Functionalization
No full textPalladium-catalyzed enantioselective C(sp3)-H functionalization reactions has attracted considerable attention due to its ability for the synthesis of enantiomerically enriched molecules and stimulation of novel retrosynthetic disconnections. Understanding the reaction mechanism, especially the stereochemical process of the reaction, is crucial for the rational design of more efficient catalytic systems. Previously, we developed a Pd(II)/sulfoxide-2-hydroxypridine (SOHP) catalytic system for asymmetric C(sp3)-H functionalization reactions. In this study, our focus is on unraveling the chemistry of chiral palladacycles involved in the Pd(II)-catalyzed enantioselective C(sp3)-H functionalization. We have isolated key palladacycle intermediates involved in the enantioselective β-C(sp3)-H arylation of carboxylic acids catalyzed by the Pd(II)/SOHP system. These palladacycles, exhibiting ligand-induced chirality, provided a significant opportunity to investigate the stereochemical process and the ligand effect in this asymmetric C-H functionalization. Our investigation revealed that the C(sp3)-H palladation step is irreversible, representing the enantioselectivity-determining step to form diastereomeric palladacycles. Ligand exchange experiments and DFT calculations provided insights into the chiral induction in palladacycle formation and the preservation of chirality in the functionalization step. This work highlights the value of chiral palladacycle chemistry in offering mechanistic insights into the Pd(II)-catalyzed asymmetric C(sp3)-H functionalization reactions
“Invisible” ligands stabilize colloidal melanin particles – the case of L-DOPA
No full textThis report details observations that the in vitro synthesis of L-DOPA-based melanin leads to a two-component material: dark-colored aggregates stabilized by colorless ligands. Despite the appearance of dissolution, the melanin materials generated behave as dispersed, colloidal particles. All dispersible materials can, in part, be aggregated and precipitated through the addition of mono- or multivalent cations but in a non-linear, concentration-dependent fashion. The addition of cationic species, at sufficiently high concentrations, fractionates the colloids into a dark precipitate and a dispersible, colorless fraction. Precipitated aggregates could be redispersed in water through the addition of sufficiently high concentrations of KCl; an additional indicator of their colloidal nature. The dispersible fraction exhibits absorbance in the UVA and UVB range of the electromagnetic spectrum, but little to no absorbance in the visible range. The fractionated melanins were characterized using liquid chromatography, UV-Vis and FT-IR spectroscopy. Based upon the results presented we suggest a model for synthetic melanins as colloidal particles built from a dark-colored core aggregate stabilized by a set of colorless ligands