Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal.

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

A unified strategy for the total syntheses of eribulin and a macrolactam analogue of halichondrin B.

A unified synthetic route for the total syntheses of eribulin and a macrolactam analog of halichondrin B is described. The key to the success of the current synthetic approach includes the employment of our reverse approach for the construction of cyclic ether structural motifs and a modified intramolecular cyclization reaction between alkyl iodide and aldehyde functionalities to establish the all-carbon macrocyclic framework of eribulin. These syntheses, together with our previous work on the total syntheses of halichondrin B and norhalichondrin B, demonstrate and validate the powerful reverse approach in the construction of cyclic ether structural motifs. On the other hand, the unified synthetic strategy for the synthesis of the related macrolactam analog provides inspiration and opportunities in the halichondrin field and related polycyclic ether areas.

Recent Advances in Small Molecule-Based Intracellular pH Probes.

Intracellular pH plays an important role in many biological and pathological processes. Small-molecule based pH probes are found to be the most effective for pH sensing because of ease of preparation, high sensitivity, and quick response. They have many advantages such as small perturbation to the functions of the target, functional adaptability, cellular component-specific localization, etc. The present review highlights the flurry of recent activity in the development of such probes. The probes are categorized based on the type of fluorophore used like quinoline, coumarin, BODIPY, rhodamine, indolium, naphthalimide, etc., and their analytical performance is discussed.

COVID-19 diagnosis system by deep learning approaches.

The novel coronavirus disease 2019 (COVID-19) has been a severe health issue affecting the respiratory system and spreads very fast from one human to other overall countries. For controlling such disease, limited diagnostics techniques are utilized to identify COVID-19 patients, which are not effective. The above complex circumstances need to detect suspected COVID-19 patients based on routine techniques like chest X-Rays or CT scan analysis immediately through computerized diagnosis systems such as mass detection, segmentation, and classification. In this paper, regional deep learning approaches are used to detect infected areas by the lungs' coronavirus. For mass segmentation of the infected region, a deep Convolutional Neural Network (CNN) is used to identify the specific infected area and classify it into COVID-19 or Non-COVID-19 patients with a full-resolution convolutional network (FrCN). The proposed model is experimented with based on detection, segmentation, and classification using a trained and tested COVID-19 patient dataset. The evaluation results are generated using a fourfold cross-validation test with several technical terms such as Sensitivity, Specificity, Jaccard (Jac.), Dice (F1-score), Matthews correlation coefficient (MCC), Overall accuracy, etc. The comparative performance of classification accuracy is evaluated on both with and without mass segmentation validated test dataset.

A Highly Convergent Total Synthesis of Norhalichondrin B.

A new synthetic strategy for the total synthesis of norhalichondrin B featuring a highly convergent approach and our recently disclosed reverse approach for the synthesis of cyclic ether structural motifs is disclosed. Resulting in the shortest route to norhalichondrin B disclosed thus far, the reported total synthesis was achieved through the synthesis of two almost equally complex fragments whose coupling and short elaboration sequence featured an essential epimerization of the C16 stereocenter occurring concurrently with a simple acid-induced deprotection, a tactic based on a prior study along the synthetic route. This unprecedented strategy within the halichondrin family of natural products could find practical application to the synthesis of other more or less complex natural or designed halichondrin analogues.

A Reverse Approach to the Total Synthesis of Halichondrin B.

A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C-O bonds first followed by C-C bond formation. Employing the Nicholas reaction to generate linear ethers as precursors for the total synthesis of halichondrin B and other members of the halichondrin and eribulin families of compounds, this novel approach provides new opportunities for the development of improved syntheses of these complex and valuable compounds. In this Article, we report the syntheses of defined fragments I, MN, EFG, and A. Fragments I and MN were then coupled and elaborated to advanced intermediate IJKLMN, which was joined with fragment EFG to afford, after appropriate elaboration and macrolactonization, the more advanced polycyclic intermediate EFGHIJKLMN. Elaboration of the latter and coupling with fragment A followed by further functionalization completed the total synthesis of halichondrin B through a short and convergent pathway.

Recent advances in the synthesis of pyrrolo[1,2-a]indoles and their derivatives.

The pyrrolo[1,2-a]indole unit is a privileged heterocycle found in numerous natural products and has been shown to exhibit diverse pharmacological properties. Thus, recent years have witnessed immense interest from the synthesis community on the synthesis of this scaffold. In light of the ever-increasing demand for pyrrolo[1,2-a]indoles in drug discovery, this review provides an overview of recent synthesis methods for the preparation of pyrrolo[1,2-a]indoles and their derivatives. The mechanistic pathway and stereo-electronic factors affecting the yield and selectivity of the product are briefly explained. Furthermore, we have attempted to demonstrate the utility of the developed methods in the synthesis of bioactive molecules and natural products, wherever offered.

Design, Synthesis, and Biological Investigation of Epothilone B Analogues Featuring Lactone, Lactam, and Carbocyclic Macrocycles, Epoxide, Aziridine, and 1,1-Difluorocyclopropane and Other Fluorine Residues.

Despite previous studies within the epothilone field, only one member of this compound family, ixabepilone, made it to approval for clinical use. Recent advances in organic synthesis and medicinal chemistry allow further optimization of lead epothilone analogues aiming to improve their potencies and other pharmacological properties as part of the quest for discovery and development of new anticancer drugs, including antibody-drug conjugates as potential targeted cancer therapies. Herein, we report the design, synthesis, and biological evaluation of a series of new epothilone B analogues equipped with novel structural motifs, including fluorine-containing residues, 12,13-difluorocyclopropyl moieties, mono- and dimethylated macrolactones, and 1-keto macrocyclic systems, as well as two N-substituted ixabepilone analogues in which the 12,13-epoxide and macrolactam NH moieties were replaced, the former with a substituted aziridine moiety and the latter with an NCO-alkyl residue (imide or carbamate). Biological evaluation of these analogues revealed a number of exceptionally potent epothilone B analogues, demonstrating the potency enhancing effects of the fluorine residues and the aziridinyl moiety within the structure of the epothilone molecule and providing new and useful structure-activity relationships within this class of compounds.

Transition from Linear to Circular Motion in Active Spherical-Cap Colloids.

Nonspherical self-propelling colloidal particles offer many possibilities for creating a variety of active motions. In this work, we report on the transition from linear to circular motion of active spherical-cap particles near a substrate. Self-propulsion is induced by self-diffusiophoresis by catalytic decomposition of hydrogen peroxide (H2O2) on one side of the particle. Asymmetric distribution of reaction products combined with the asymmetric shape of the particle gives rise to two types of motions depending upon the relative orientation of the particle with respect to the underlying substrate. At a low concentration of H2O2, linear active motion is observed, whereas increasing the H2O2 concentration leads to persistent circular motion. However, the speed of self-propulsion is nearly independent of the size of the particle. The study demonstrates the use of nonspherical particles to create linear and circular motion by varying the fuel concentration.

Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition Cascade for the Synthesis of Ketals.

A transition metal free, acid promoted cascade hydroalkoxylation-formal [4+2] cycloaddition of various alkynols with salicylaldehyde is demonstrated for the synthesis of tetrahydrofurano/pyrano-chromenes and spiroketals. In general, alkynols underwent hydroalkoxylations in an endo-dig manner when internal alkynes were used to furnish the heteroannular ketals, whereas terminal alkynes proceeded in an exo-dig fashion leading to spiroketals. The study revealed that intramolecular hydroalkoxylation of alkynols is a preferred path over a generation of oxonium ions when coupling partner is salicylaldehyde. This metal-free transformation provides a new avenue for the stereoselective synthesis of tetrahydrofurano- and pyrano-chromenes in an expeditious manner.

Staggered Linear Assembly of Spherical-Cap Colloids.

Linear assembly of colloidal particles is of fundamental interest in visualizing polymer dynamics and living organisms. We have developed a fluid-fluid interface-based method to synthesize spherical-cap polymeric latex particles. These particles are shown to spontaneously self-assemble in zigzag arrangement. The linear assembly is induced due to the shape anisotropy (one side is curved and the other side is nearly flat) and heterogeneous charge distribution on the particle surfaces. The necessities of these conditions are justified within the framework of DLVO theory. Spherical-cap particles of various size and aspect ratio reproduced the observed linear assembly, thus demonstrating the robustness of the self-assembly mechanism. While these types of assemblies are observed in spherical particles using microfluidic devices or electric field, the proposed approach is rather facile and does not require any external field. These novel assemblies could be potentially useful to understand kinetics of nucleation and growth of amyloidogenic proteins and to prepare artificial swimming microorganisms.

Lewis Acid Promoted Oxonium Ion Driven Carboamination of Alkynes for the Synthesis of 4-Alkoxy Quinolines.

Lewis acid mediated multisegment coupling cascade is designed for the synthesis of densely substituted 4-alkoxy quinolines via an oxonium ion triggered alkyne carboamination sequence involving C-C and C-N bond formations. Cyclic ether fused-quinolines could also be accessed using this fast, operationally simple, high yielding, chemoselective and functional group tolerant method. Versatility and utility of this methodology is demonstrated by postfunctionalization of products obtained and its use in synthesis of potent drug molecules.

Synthesis of non-spherical patchy particles at fluid-fluid interfaces via differential deformation and their self-assembly.

Non-spherical patchy particles are potential candidates as building blocks for the design of target colloidal structures via spontaneous self-organization. We report a facile scheme to synthesize non-spherical particles with patchy electrostatic interactions. In this method, charged spherical latex particles such as polystyrene (PS) are deformed unequally at an oil-water interface due to heating and partial swelling. The spherical particles then evolve into non-spherical shapes such as 'acorn-like' and 'idly-like'. We explain the mechanism of differential deformation by comparing the heat of viscous dissipation and the interfacial energies. Furthermore, if oppositely charged additives such as the cetyltrimethylammonium bromide (CTAB) surfactant or silica nanoparticles are present in water (subphase), electrostatic attraction leads to adsorption of these species on the PS surface exposed to water. As a result, one side of the particles is selectively functionalized, while the other side remains unaltered. As the latex particles are negatively charged initially, this method yields particles that are non-spherical in shape and with negative charges on one side and positive charges on the other side. The degree of shape deformation and patch coverage can be varied by choosing different surface active additives. We extend this approach to curved interfaces and demonstrate a high throughput emulsion based approach for the synthesis of such particles. Self-assembly of these particles shows interesting structures such as linear, branched polymeric or worm-like chains and micelle-like spherical aggregates. These shape anisotropic particles with orientation specific interactions that mimic bio-macromolecular systems can be further explored for self-assembly into hierarchical mesoscale structures.

Exploiting anisotropic particle shape to electrostatically assemble colloidal molecules with high yield and purity.

HYPOTHESIS: Colloidal molecules with anisotropic shapes and interactions are powerful model systems for deciphering the behavior of real molecules and building units for creating materials with designed properties. While many strategies for their assembly have been developed, they typically yield a broad distribution or are limited to a specific type. We hypothesize that the shape and relative sizes of colloidal particles can be exploited to efficiently direct their assembly into colloidal molecules of desired valence. EXPERIMENTS: We exploit electrostatic self-assembly of negatively charged spheres made from either polystyrene or silica onto positively charged hematite cubes. We thoroughly analyze the role of the shape and size ratio of particles on the cluster size and yield of colloidal molecules. FINDINGS: Using a combination of experiments and simulations, we demonstrate that cubic particle shape is crucial to generate high yields of distinct colloidal molecules over a wide variety of size ratios. We find that electrostatic repulsion between the satellite spheres is important to leverage the templating effect of the cubes, leading the spheres to preferentially assemble on the facets rather than the edges and corners of the cube. The sixfold symmetry of cubes favors the assembly of molecules with six, four, and two satellite spheres at appropriate size ratios and interaction strength. Furthermore, we reveal that our protocol is not affected by the specific choice of the material of the colloidal particles. Finally, we show that the permanent magnetic dipole moment of the hematite cubes can be utilized to separate colloidal molecules from non-assembled satellite particles. Our simple and effective strategy might be extended to other templating particle shapes, thereby greatly expanding the library of colloidal molecules that can be achieved with high yield and purity.

Flexible Colloidal Molecules with Directional Bonds and Controlled Flexibility.

Colloidal molecules are ideal model systems for mimicking real molecules and can serve as versatile building blocks for the bottom-up self-assembly of flexible and smart materials. While most colloidal molecules are rigid objects, the development of colloidal joints has made it possible to endow them with conformational flexibility. However, their unrestricted range of motion does not capture the limited movement and bond directionality that is instead typical of real molecules. In this work, we create flexible colloidal molecules with an in situ controllable motion range and bond directionality by assembling spherical particles onto cubes functionalized with complementary surface-mobile DNA. By varying the sphere-to-cube size ratio, we obtain colloidal molecules with different coordination numbers and find that they feature a constrained range of motion above a critical size ratio. Using theory and simulations, we show that the particle shape together with the multivalent bonds creates an effective free-energy landscape for the motion of the sphere on the surface of the cube. We quantify the confinement of the spheres on the surface of the cube and the probability to change facet. We find that temperature can be used as an extra control parameter to switch in situ between full and constrained flexibility. These flexible colloidal molecules with a temperature switching motion range can be used to investigate the effect of directional yet flexible bonds in determining their self-assembly and phase behavior, and may be employed as constructional units in microrobotics and smart materials.

Augmented Reality and Virtual Reality Transforming Spinal Imaging Landscape: A Feasibility Study.

This article discusses a systematic review of the state-of-the-art on augmented reality (AR) and virtual reality (VR) in spinal navigation, where early clinical validations have shown promising outlook on accuracy and scalability parameters. The objective of this research is to evaluate clinical relevance for AR-VR enabled spinal surgical technologies and develop an economic feasibility model for stakeholders, such as patients, hospitals, and research organizations with technology adoption. From the influencing parameters, we identified the research gaps that can be explored going forward and a list of high priority research challenges that could provide an attractive research and development investment case for industry players.

Cascade Radical Cyclization on Alkynyl Vinylogous Carbonates for the Divergent Synthesis of Tetrasubstituted Furans and Dihydrofurans.

A single alkynyl vinylogous carbonate was elaborated to tetrasubstituted furan or dihydrofuran via a cascade inter-intramolecular radical reaction by changing the radical being added. The strategy could be used in the synthesis of polycyclic heterocycles as well as bis-furan exhibiting atropisomerism. Installation of a new furan motif on the existing one was feasible by iteration. Stannyl dihydrofuran derivative was used in Stille coupling, whereas intramolecular Friedel-Crafts acylation on the furan gave furanonaphthol.

Homogeneous Catalysis: A Powerful Technology for the Modification of Important Biomolecules.

Homogeneous catalysis plays an important and ubiquitous role in the synthesis of simple and complex molecules, including drug compounds, natural products, and agrochemicals. In recent years, the wide-reaching importance of homogeneous catalysis has made it an indispensable tool for the modification of biomolecules, such as carbohydrates (sugars), amino acids, peptides, nucleosides, nucleotides, and steroids. Such a synthetic strategy offers several advantages, which have led to the development of new molecules of biological relevance at a rapid rate relative to the number of available synthetic methods. Given the powerful nature of homogeneous catalysis in effecting these synthetic transformations, this Focus Review has been compiled to highlight these important developments.

Cascade Radical Cyclization of N-Propargylindoles: Substituents Dictate Stereoselective Formation of N-Fused Indolines versus Indoles.

An efficient protocol for the synthesis of pyrrolo[1,2-a]indole derivatives having sulfide functionality using cascade radical cyclization on propargylindole is described. The nature of the substituents at the propargylic carbon bearing nitrogen of the indole has a profound effect on the rate, yield, and nature of the product obtained by the cascade radical cyclization. An expeditious one-pot route for cascade radical cyclization-desulfurization is also presented. Products obtained were elaborated to the core of the putative structure of the yuremamine and indoline derivative with five contiguous stereocenters.

Lewis Acid Mediated Cascade Friedel-Craft/Alkyne Indol-2-yl Cation Cyclization/Vinyl Cation Trapping for the Synthesis of N-Fused Indole Derivatives.

A Lewis acid promoted cascade Friedel-Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping for an efficient and divergent synthesis of N-fused indoles is developed. The present study illustrates the first example of an alkyne as a nucleophile on the less explored indol-2-yl cation. The method efficiently affords pharmaceutically important pyrrolizino-quinolines and complex fused indole derivatives in high yields.