Discovery of novel SOS1 inhibitors using machine learning.

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 µg mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

Exploring the Dual Functions of Distal Acyl Group Direction in Various Nucleophilic Environments.

A universal glycosylation strategy could significantly simplify glycoside synthesis. One approach to achieving this goal is through acyl group direction for the corresponding 1,2-, 1,3-, 1,4-, or 1,6-trans glycosylation; however, this approach has been challenging for glycosidic bonds that require distal equatorial-acyl group direction. We developed an approach in weakly nucleophilic environments for selective 1,4-trans glycosylation directed by the equatorial-4-O-acyl group. Here, we explored this condition in other distal acyl groups and found that, besides 1,n-trans direction, acyl groups also mediated hydrogen bonding between acyl groups and alcohols. The latter showed a diverse effect and classified the acyl group direction into axial and equatorial categories. Corresponding glycosylation conditions were distinguished as guidance for acyl group direction from either category. Hence, acyl group direction may serve as a general glycosylation strategy.

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones.

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides.

Nucleation Regulation and Mesoscopic Dielectric Screening in α-FAPbI3.

While significant advancements in power conversion efficiencies (PCEs) of α-FAPbI3perovskite solar cells (PSCs) have been made, attaining controllable perovskite crystallization is still a considerable hurdle. This challenge stems from the initial formation of δ-FAPbI3, a more energetically stable phase than the desired black α-phase, during film deposition. This disrupts the heterogeneous nucleation of α-FAPbI3, causing the formation of mixed phases and defects. To this end, polarity engineering using molecular additives, specifically ((methyl-sulfonyl)phenyl)ethylamines (MSPEs) are introduced. The findings reveal that the interaction of PbI2-MSPEs-FAI intermediates is enhanced with the increased polarity of MSPEs, which in turn expedites the nucleation of α-FAPbI3. This leads to the development of high-quality α-FAPbI3 films, characterized by vertical crystal orientation and reduced residual stresses. Additionally, the increased dipole moment of MSPE at perovskite grain boundaries attenuates Coulomb attractions among charged defects and screens carrier capture process, thereby diminishing non-radiative recombination. Utilizing these mechanisms, PSCs treated with highly polar 2-(4-MSPE) achieve an impressive PCE of 25.2% in small-area devices and 20.5% in large-area perovskite solar modules (PSMs) with an active area of 70 cm2. These results demonstrate the effectiveness of this strategy in achieving controllable crystallization of α-FAPbI3, paving the way for scalable-production of high-efficiency PSMs.

Strategies for utilizing covalent organic frameworks as host materials for the integration and delivery of bioactives.

Covalent organic frameworks (COFs), a new and developing class of porous framework materials, are considered a type of promising carrier for the integration and delivery of bioactives, which have diverse fascinating merits, such as a large specific surface area, designable and specific porosity, stable and orderly framework structure, and various active sites. However, owing to the significant differences among bioactives (including drugs, proteins, nucleic acid, and exosomes), such as size, structure, and physicochemical properties, the interaction between COFs and bioactives also varies. In this review, we firstly summarize three strategies for the construction of single or hybrid COF-based matrices for the delivery of cargos, including encapsulation, covalent binding, and coordination bonding. Besides, their smart response release behaviors are also categorized. Subsequently, the applications of cargo@COF biocomposites in biomedicine are comprehensively summarized, including tumor therapy, central nervous system (CNS) modulation, biomarker analysis, bioimaging, and anti-bacterial therapy. Finally, the challenges and opportunities in this field are briefly discussed.

ß-l-Rhamnosylation and ß-d-Mannosylation Mediated by 4-O-Ester Groups in a Weakly Nucleophilic Environment.

eq-4-O-Acyl group directed ß-rhamnosylation and ß-mannosylation are achieved in a carborane or BARF anion formed weakly nucleophilic environment with the assistance of a 2,3-orthocarbonate group. The 4-O-acyl group plays a critical role in directing the ß-selectivity, and the weakly coordinating anion is essential to amplify this direction. The orthocarbonate group could be readily removed with 1,3-propanediol in the presence of BF3·Et2O.

Multideuteration of Nitroaromatics by Silver-Catalyzed Hydrogen-Isotope Exchange.

Silver-catalyzed deuteration of nitroaromatics has been achieved using D2O as the deuterium source. Distinct from the well-established directing group-guided hydrogen-isotope exchange, this protocol showed an interesting deuteration pattern, where considerable deuterium accumulation was observed around the aromatic rings. Controlling experiments suggested that the deuteration was initiated by a silver-promoted C-H activation. Therefore, a tentative two-stage deuteration mechanism involving aryl-silver species was proposed to explain the deuteration on meta- and para-positions.

Regioselective Cycloaddition and Substitution Reaction of Tertiary Propargylic Alcohols and Heteroareneboronic Acids via Acid Catalysis.

We report an acid-catalyzed formal cycloaddition and dehydrative substitution reaction of tertiary propargylic alcohols and heteroareneboronic acids. The properties of the substituents on the alkynyl moiety determines the regioselectivity of the reaction, which could selectively construct fused heterocycles, tetrasubstituted allenes, or 1,3-dienes. This reaction proceeds efficiently with a wide array of substrate scope in up to 89% yield. A significant advantage of this protocol is the transition-metal-free and mild conditions needed.

Potassium tert-butoxide promoted regioselective deuteration of pyridines.

A regioselective deuteration at the ß- and γ-position of pyridines is reported. Efficient deuteration occurred with a combination of KOtBu and DMSO-d6, replenishing the prevailing α-deuteration of the pyridine systems. Preliminary mechanistic studies suggested that the dimsyl carbanion acts as one of the key intermediates.

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1.

A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination (R2) of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules.

Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange.

A practical and scalable ortho-selective deuteration of aromatic aldehydes was accomplished by Pd-catalyzed hydrogen isotope exchange with deuterium oxide as an inexpensive deuterium source. The use of tert-leucine as a transient directing group facilitates the exchange, affording a wide range of ortho-deuterated aromatic aldehydes with deuterium incorporation up to 97%. The control experiments suggest that the addition of silver trifluoroacetate resists the unexpected reduction of Pd(II), while the theoretical study indicates a rapid reversible concerted metalation-deprotonation process.

Understanding the Effect of Sequential Deposition Processing for High-Efficient Organic Photovoltaics to Harvest Sunlight and Artificial Light.

As the market of the Internet of Things (IoT) increases, great attention has been paid to the development of high-efficient organic photovoltaics (OPVs) utilizing artificial light. However, in a real indoor condition, the power density contribution of the artificial light cannot exceed 35% in the combination of indoor and outdoor irradiation, which indicates that the illumination of sunlight cannot be ignored during daytime. Hence, it is urgent to develop high-efficient OPVs in indoor conditions taking into account both sunlight and artificial light. In this work, a novel asymmetric molecule TB-4F was synthesized to trade-off the absorption spectrum that can be applied under both artificial light and sunlight. In conventional bulk-heterojunction (C-BHJ), it was figured out that due to nonoptimal morphology some carriers failed to be efficiently collected. Herein, a sequential deposition bulk-heterojunction (SD-BHJ) as an alternative fabrication method successfully enhanced the performance of OPVs, under both artificial light and sunlight, which was attributed to the favorable microstructure being vertically distributed in the active layer. Notably, the PCE was significantly increased by 25% for SD-BHJ compared to C-BHJ under artificial light, owing to the strong effect of trap-assisted recombination and dark current on PCE in the condition of low carrier density. Our result indicates that an asymmetric molecule with a blue-shifted spectrum fabricated by SD-BHJ can be a promising candidate that can be applied in indoor environments to harvest sunlight and artificial light simultaneously.

Synthesis of an isomer of lycoplanine A via cascade cyclization to construct the spiro-N,O-acetal moiety.

An isomer of lycoplanine A with a 6/10/5/5 tetracyclic skeleton was synthesized using D-A reaction and cascasde reaction to respectively construct the [9.2.2] pentadecane skeleton and the challenging 1-oxa-6-azaspiro[4.4]nonane spirocenter. Morever, detailed DFT calculations were conducted to explain the selectivity in the D-A reaction. This study may provide sufficient experience for the total synthesis of lycoplanine A and other alkaloids with similar spiro-N,O-acetal cores.

C-N and C-O Bond Formation in Copper-Catalyzed/Mediated sp3 C-H Activation: Mechanistic Studies from Experimental and Computational Aspects.

Mechanistic studies on Cu-catalyzed/mediated sp3 C-H amidation and acetoxylation are investigated from experimental and computational aspects. The concerted metalation-deprotonation (CMD) mechanism rather than a radical-involved pathway is proved to occur in amidation and acetoxylation reactions, and this is the rare example of the CMD mechanism involved in the more challenging sp3 C-H activations. Theoretical calculations demonstrated that CMD is the rate-determining step either for methylic or benzylic positions in amidation and acetoxylation reactions, and intermolecular nucleophilic addition of acetate anions is more favorable than the ring opening of ß-lactams and intramolecular acetoxylation. These mechanistic studies on the divergent and condition-dependent product formation are critical for developing Cu-promoted C-H functionalization via the CMD mechanism.

Bio-processing of algal bio-refinery: a review on current advances and future perspectives.

Microalgae biomass contains various useful bio-active components. Microalgae derived biodiesel has been researched for almost two decades. However, sole biodiesel extraction from microalgae is time-consuming and is not economically feasible due to competitive fossil fuel prices. Microalgae also contains proteins and carbohydrates in abundance. Microalgae are likewise utilized to extract high-value products such as pigments, anti-oxidants and long-chain polyunsaturated fatty acids which are useful in cosmetic, pharmaceutical and nutraceutical industry. These compounds can be extracted simultaneously or sequentially after biodiesel extraction to reduce the total expenditure involved in the process. This approach of bio-refinery is necessary to promote microalgae in the commercial market. Researchers have been keen on utilizing the bio-refinery approach to exploit the valuable components encased by microalgae. Apart from all the beneficial components housed by microalgae, they also help in reducing the anthropogenic CO2 levels of the atmosphere while utilizing saline or wastewater. These benefits enable microalgae as a potential source for bio-refinery approach. Although life-cycle analysis and economic assessment do not favor the use of microalgae biomass feedstock to produce biofuel and co-products with the existing techniques, this review still aims to highlight the beneficial components of microalgae and their importance to humans. In addition, this article also focuses on current and future aspects of improving the feasibility of bio-processing for microalgae bio-refinery.

Heliaquanoids A-E, Five Sesquiterpenoid Dimers from Inula helianthus-aquatica.

Heliaquanoid A (1), the first exo-2,4-linked Diels-Alder adduct between a pseudoguaianolide dienophile and a guaianolide diene, and heliaquanoids B-E (2-5), four new 2,4-linked Diels-Alder adducts between a xanthanolide dienophile and a guaianolide diene, were isolated from stems and leaves of Inula helianthus-aquatica. Their structures were determined by NMR spectroscopy, a modified Mosher's method, electronic circular dichroism, and X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 7.5 and 4.9 µM, respectively.

Biosynthesis of Providencin: Understanding Photochemical Cyclobutane Formation with Density Functional Theory.

The unique structure of furanocembranoid natural product providencin has stimulated biosynthetic hypotheses, especially concerning the formation of its cyclobutanol ring. One such hypothesis involves a photochemically induced Norrish-Yang cyclization in bipinnatin E. We have used computations to assess the feasibility and the stereochemical outcome of this proposed biosynthetic transformation. Density functional theory calculations reveal that the proposed Norrish-Yang cyclization in bipinnatin E is possible and that the stereoselectivity of this step is consistent with that of the natural product.

Total syntheses of shizukaols A and E.

Shizukaols possess a common heptacyclic framework containing more than ten contiguous stereocenters and potential biological activities. Here we report that the total syntheses of shizukaols A (1) and E (2), two lindenane-type dimers from the Chloranthaceae family, are achieved via a modified biomimetic Diels-Alder reaction. The common crucial biomimetic diene 23 and ethylene species (6, 17) are obtained through either a highly Z-selective olefination of α-siloxy ketone with ynolate anions or an intramolecular Horner-Wadsworth-Emmons olefination from commercially available Wieland-Miescher ketone (7). This synthetic approach here opens up practical avenues for the total syntheses of the intriguing Chloranthaceae family members, as well as the understanding of their relevant biological action in nature.