Advancing Nitrile-Aminothiol Strategy for Dual and Sequential Bioconjugation.

Nitrile-aminothiol conjugation (NATC) stands out as a promising biocompatible ligation technique due to its high chemo-selectivity. Herein we investigated the reactivity and substrate scope of NAT conjugation chemistry, thus developing a novel pH dependent orthogonal NATC as a valuable tool for chemical biology. The study of reaction kinetics elucidated that the combination of heteroaromatic nitrile and aminothiol groups led to the formation of an optimal bioorthogonal pairing, which is pH dependent. This pairing system was effectively utilized for sequential and dual conjugation. Subsequently, these rapid (≈1 h) and high yield (>90%) conjugation strategies were successfully applied to a broad range of complex biomolecules, including oligonucleotides, chelates, small molecules and peptides. The effectiveness of this conjugation chemistry was demonstrated by synthesizing a fluorescently labelled antimicrobial peptide-oligonucleotide complex as a dual conjugate to imaging in live cells. This first-of-its-kind sequential NATC approach unveils unprecedented opportunities in modern chemical biology, showcasing exceptional adaptability in rapidly creating structurally complex bioconjugates. Furthermore, the results highlight its potential for versatile applications across fundamental and translational biomedical research.

Gold-Catalyzed Alkoxy-Carbonylation of Aryl and Vinyl Iodides.

Herein, for the first time, we disclose the gold-catalyzed alkoxy-carbonylation of aryl and vinyl iodides utilizing ligand-enabled Au(I)/Au(III) redox catalysis. The present methodology is found to be general, efficient, employs mild reaction conditions and showcases a broad substrate scope even with structurally complex molecules. Density functional theory (DFT) calculations revealed mechanistic pathways distinct from those of conventional transition metal-catalyzed carbonylation reactions.

Gold-Catalyzed Arylative Cope Rearrangement.

Cope rearrangements have garnered significant attention owing to their ability to undergo structural reorganization in stereoselective manner. While substantial advances have been achieved over decades, these rearrangements remained applicable exclusively to parent 1,5-hexadienes. Herein, we disclose the gold-catalyzed arylative Cope rearrangement of 1,6-heptadienes via a cyclization-induced [3,3]-rearrangement employing ligand-enabled gold redox catalysis. Detailed mechanistic investigations including several control experiments, cross-over experiment, HRMS analysis, 31P NMR and DFT studies have been performed to underpin the mechanism.

Gold-Catalyzed Heck Reaction.

Herein, we report a gold-catalyzed Heck reaction facilitated by the ligand-enabled Au(I)/Au(III) redox catalysis. The elementary organometallic steps such as migratory insertion and ß-hydride elimination have been realized in the catalytic fashion for the first time in gold chemistry. The present methodology not only overcomes the limitations of previously known transition metal-catalyzed Heck reactions such as the requirement of specialized substrates and formation of a mixture of regioisomeric products as a result of the undesirable chain-walking process but also offers complementary regioselectivity as compared to other transition metal catalysis.

Monitoring and modelling the glutamine metabolic pathway: a review and future perspectives.

BACKGROUND: Analysis of the glutamine metabolic pathway has taken a special place in metabolomics research in recent years, given its important role in cell biosynthesis and bioenergetics across several disorders, especially in cancer cell survival. The science of metabolomics addresses the intricate intracellular metabolic network by exploring and understanding how cells function and respond to external or internal perturbations to identify potential therapeutic targets. However, despite recent advances in metabolomics, monitoring the kinetics of a metabolic pathway in a living cell in situ, real-time and holistically remains a significant challenge. AIM: This review paper explores the range of analytical approaches for monitoring metabolic pathways, as well as physicochemical modeling techniques, with a focus on glutamine metabolism. We discuss the advantages and disadvantages of each method and explore the potential of label-free Raman microspectroscopy, in conjunction with kinetic modeling, to enable real-time and in situ monitoring of the cellular kinetics of the glutamine metabolic pathway. KEY SCIENTIFIC CONCEPTS: Given its important role in cell metabolism, the ability to monitor and model the glutamine metabolic pathways are highlighted. Novel, label free approaches have the potential to revolutionise metabolic biosensing, laying the foundation for a new paradigm in metabolomics research and addressing the challenges in monitoring metabolic pathways in living cells.

Divergent Gold Catalysis: Unlocking Molecular Diversity through Catalyst Control.

The catalyst-directed divergent synthesis, commonly termed as "divergent catalysis", has emerged as a promising technique as it allows chartering of structurally distinct products from common substrates simply by modulating the catalyst system. In this regard, gold complexes emerged as powerful catalysts as they offer unique reactivity profiles as compared to various other transition metal catalysts, primarily due to their salient electronic and geometrical features. Owing to the tunable soft π-acidic nature, gold catalysts not only evolved as superior contenders for catalyzing the reactions of alkynes, alkenes, and allenes but also, more intriguingly, have been found to provide divergent reaction pathways over other π-acid catalysts such as Ag, Pt, Pd, Rh, Cu, In, Sc, Hg, Zn, etc. The recent past has witnessed a renaissance in such examples wherein, by choosing gold catalysts over other transition metal catalysts or by fine-tuning the ligands, counteranions or oxidation states of the gold catalyst itself, a complete reactivity switch was observed. However, reviews documenting such examples are sporadic; as a result, most of the reports of this kind remained scattered in the literature, thereby hampering further development of this burgeoning field. By conceptualizing the idea of "Divergent Gold Catalysis (DGC)", this review aims to consolidate all such reports and provide a unified approach necessary to pave the way for further advancement of this exciting area. Based on the factors governing the divergence in product formation, an explicit classification of DGC has been provided. To gain a fundamental understanding of the divergence in observed reactivities and selectivities, the review is accompanied by mechanistic insights at appropriate places.

Gold-Catalyzed 1,2-Dicarbofunctionalization of Alkynes with Organohalides.

Herein, we report the first gold-catalyzed 1,2-dicarbofunctionalization of alkynes using organohalides as non-prefunctionalized coupling partners. The mechanism of the reaction involves an oxidative addition/π-activation mechanism in contrast to the migratory insertion/cis-trans isomerization pathway that is predominantly observed with other transition metals yielding products with anti-selectivity. Mechanistic insights include several control experiments, NMR studies, HR-MSMS analyses, and DFT calculations that strongly support the proposed mechanism.

Electrochemical Gold-Catalyzed 1,2-Difunctionalization of C-C Multiple Bonds.

Herein, we disclose the first report of 1,2-difunctionalization of C-C multiple bonds using electrochemical gold redox catalysis. By adopting the electrochemical strategy, the inherent π-activation and cross-coupling reactivity of gold catalysis are harnessed to develop the oxy-alkynylation of allenoates under external-oxidant-free conditions. Detailed mechanistic investigations such as 31 P NMR, control experiments, mass studies, and cyclic voltammetric (CV) analysis have been performed to support the proposed reaction mechanism.

Unlocking the Chain-Walking Process in Gold Catalysis.

The successful realization of gold-catalyzed chain-walking reactions, facilitated by ligand-enabled Au(I)/Au(III) redox catalysis, has been reported for the first time. This breakthrough has led to the development of gold-catalyzed annulation reaction of alkenes with iodoarenes by leveraging the interplay of chain-walking and π-activation reactivity mode. The reaction mechanism has been elucidated through comprehensive experimental and computational studies.

Enantioselective Au(I)/Au(III) Redox Catalysis Enabled by Chiral (P,N)-Ligands.

Presented herein is the first report of enantioselective Au(I)/Au(III) redox catalysis, enabled by a newly designed hemilabile chiral (P,N)-ligand (ChetPhos). The potential of this concept has been demonstrated by the development of enantioselective 1,2-oxyarylation and 1,2-aminoarylation of alkenes which provided direct access to the medicinally relevant 3-oxy- and 3-aminochromans (up to 88% yield and 99% ee). DFT studies were carried out to unravel the enantiodetermining step, which revealed that the stronger trans influence of phosphorus allows selective positioning of the substrate in the C2-symmetric chiral environment present around nitrogen, imparting a high level of enantioselectivity.

AIEgens Based on Anion-π+ Interactions: Design, Synthesis, Photophysical Properties, and Their Applications in Material Science and Biology.

The design of novel aggregation-induced emission luminogens (AIEgens), has generally been facilitated by disrupting the possibility of π-π stacking. The recent literature describes a novel strategy to design AIEgens by introducing anion-π+ interactions to prevent the detrimental π-π stacking. This new strategy provides access to intrinsically charged AIEgens whose photophysical properties can be tuned either by incorporating different substituents on the π-molecular scaffold to modulate the acidity for tuning the interaction energy between a π-acceptor and counter-anions. This concept article provides a brief overview of the field, focusing on the synthesis of AIEgens, their photophysical properties, crystallography studies and their applications in live cell fluorescence imaging.

Enantioselective C-H Functionalization Reactions under Gold Catalysis.

Transition metal-catalyzed enantioselective functionalization of ubiquitous C-H bonds has proven to be promising field as it offers the construction of chiral molecular complexity in a step- and atom-economical manner. In recent years, gold has emerged as an attractive contender for catalyzing such reactions. The unique reactivities and selectivities offered by gold catalysts have been exploited to access numerous asymmetric transformations based on gold-catalyzed C-H functionalization processes. Herein, this review critically highlights the major advances and discoveries made in the enantioselective C-H functionalization under gold catalysis which is accompanied by mechanistic insights at appropriate places.

Interplay of Anion-π+ and π+ -π+ Interactions in Novel Pyrido[2,1-a]isoquinolinium-Based AIEgens - Substituent- and Counterion-Dependent Fluorescence Modulation and Applications in Live Cell Mitochondrial Imaging.

Recently, the concept of anion-π+ interactions has witnessed unique applications in the field of AIEgen development. In this contribution, we disclose a consolidated study of a library of N-doped ionic AIEgens accessed through silver-mediated cyclization of pyridino-alkynes. A thorough photophysical, computational and crystallographic study has been conducted to rationalize the observed substituent- and counterion-dependent fluorescence properties of these luminogens. We further elucidate the prominent role of anion-π+ interactions, π+ -π+ interactions and other non-covalent interactions, in inhibiting the undesired ACQ effect. Finally, we have also demonstrated the application of selected AIEgens for imaging of mitochondria in live cells.

A comparative evaluation of the efficacy of intralesional tranexamic acid versus platelet rich plasma in the treatment of melasma.

Melasma is a benign, acquired disorder of hyperpigmentation commonly affecting the face. Though easily diagnosable, a tangible treatment for melasma still remains elusive. Our aim was to compare the therapeutic efficacy and safety of tranexamic acid (TXA) and platelet rich plasma (PRP) microinjections in treating patients with melasma. In total, 40 patients with melasma (10 males, 30 females; age range: 21-54 years) were enrolled, and randomly assigned to one of the two groups consisting of 20 patients each. Group A (3 males, 17 females) received intradermal microinjections of TXA (4 mg/ml) and group B (5 males, 15 females) received intradermal microinjections of PRP, once every 4 weeks for a total of five treatment sessions. Clinical images were taken at each visit and improvement in melasma was evaluated using both melasma area severity index (MASI) and modified melasma area severity index (mMASI) scoring systems. Percentage reduction of both MASI and mMASI scores were also assessed at each visit, and the grade of melasma improvement was accordingly outlined for each patient. The study was completed by 18 patients in group A (TXA) and 15 patients in group B (PRP). In group A, both MASI and mMASI scores reduced significantly from 16.6 ± 9.227 at baseline to 10.028 ± 8.07 at end point; and 8.885 ± 5.418 at baseline to 4.639 ± 3.863 at end point, respectively (p value <0.01). Similarly in group B significant reduction in both scores were observed at the end of treatment. MASI declined from 20.42 ± 7.979 to 12.253 ± 7.37; and mMASI plummeted to 5.613 ± 3.98 from 10.673 ± 4.642 (p value <0.01). In group A, the difference in mean reduction of MASI and mMASI from baseline to end point was 6.572 ± 4.528 and 4.211 ± 2.647, respectively. In group B, the difference in mean reduction of both scores at the end of treatment reflected values of 8.167 ± 4.975(MASI) and 5.06 ± 2.977 (mMASI). No significant adverse effects were encountered in both treatment arms during the entire duration of study. Both TXA and PRP microinjections were found to be effective and safe therapeutic options for melasma, providing rapid and substantial improvement even when used as standalone therapies. Although PRP mesotherapy was found to be slightly better than intradermal TXA in our study, the results were not significant statistically.

The interplay of carbophilic activation and Au(I)/Au(III) catalysis: an emerging technique for 1,2-difunctionalization of C-C multiple bonds.

Gold complexes have emerged as the catalysts of choice for various functionalization reactions of C-C multiple bonds due to their inherent carbophilic nature. In a parallel space, efforts to realize less accessible cross-coupling reactivity have led to the development of various strategies that facilitate the arduous Au(I)/Au(III) redox cycle. The interplay of the two important reactivity modes encountered in gold catalysis, namely carbophilic activation and Au(I)/Au(III) catalysis, has allowed the development of a novel mechanistic paradigm that sponsors 1,2-difunctionalization reactions of various C-C multiple bonds. Interestingly, the reactivity as well as selectivity obtained through this interplay could be complementary to that obtained by the use of various other transition metals that mainly involved the classical oxidative addition/migratory insertion pathways. The present review shall comprehensively cover all the 1,2-difunctionalization reactions of C-C multiple bonds that have been realized by the interplay of the two important reactivity modes and categorized on the basis of the method that has been employed to foster the Au(I)/Au(III) redox cycle.

Defining the "Metastasome": Perspectives from the genome and molecular landscape in colorectal cancer for metastasis evolution and clinical consequences.

Metastasis still poses the highest challenge for personalized therapy in cancer, partly due to a still incomplete understanding of its molecular evolution. We recently presented the most comprehensive whole-genome study of colorectal metastasis vs. matched primary tumors and suggested novel components of disease progression and metastasis evolution, some of them potentially relevant for targeted therapy. In this review, we try to put these findings into perspective with latest discoveries of colleagues and recent literature, and propose a systematic international team effort to collectively define the "metastasome", a term we introduce to summarize all genomic, epigenomic, transcriptomic, further -omic, molecular and functional characteristics rendering metastases different from primary tumors. Based on recent discoveries, we propose a revised metastasis model for colorectal cancer which is based on a common ancestor clone, early dissemination but flexible early or late stage clonal separation paralleling stromal interactions. Furthermore, we discuss hypotheses on site-specific metastasis, colorectal cancer progression, metastasis-targeted diagnosis and therapy, and metastasis prevention based on latest metastasome data.

Simulations of octapeptin-outer membrane interactions reveal conformational flexibility is linked to antimicrobial potency.

The octapeptins are lipopeptide antibiotics that are structurally similar to polymyxins yet retain activity against polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant infections. However, the basis of their unique activity is unclear because of the difficulty in generating high-resolution experimental data of the interaction of antimicrobial peptides with lipid membranes. To elucidate these structure-activity relationships, we employed all-atom molecular dynamics simulations with umbrella sampling to investigate the conformational and energetic landscape of octapeptins interacting with bacterial outer membrane (OM). Specifically, we examined the interaction of octapeptin C4 and FADDI-115, lacking a single hydroxyl group compared with octapeptin C4, with the lipid A-phosphoethanolamine modified OM of Acinetobacter baumannii Octapeptin C4 and FADDI-115 both penetrated into the OM hydrophobic center but experienced different conformational transitions from an unfolded to a folded state that was highly dependent on the structural flexibility of their respective N-terminal fatty acyl groups. The additional hydroxyl group present in the fatty acyl group of octapeptin C4 resulted in the molecule becoming trapped in a semifolded state, leading to a higher free energy barrier for OM penetration. The free energy barrier for the translocation through the OM hydrophobic layer was ∼72 kcal/mol for octapeptin C4 and 62 kcal/mol for FADDI-115. Our results help to explain the lower antimicrobial activity previously observed for octapeptin C4 compared with FADDI-115 and more broadly improve our understanding of the structure-function relationships of octapeptins. These findings may facilitate the discovery of next-generation octapeptins against polymyxin-resistant Gram-negative 'superbugs.'

1,2-Aminofunctionalization Reactions of Pyridino-Alkynes via Carbophilic Activation.

Transition metal-catalyzed 1,2-difunctionalization reactions of alkynes have emerged as a powerful tool to forge carbon-carbon and carbon-heteroatom bonds for the rapid synthesis of polyfunctionalized molecular scaffolds. In this regard, our group has persistently been developing transition metal-mediated 1,2-aminofunctionalization reactions of alkynes through a rationally designed pyridino-alkyne core by utilizing the carbophilic activation strategy. In this account, we present an array of such 1,2-aminofunctionalization reactions which have been successfully executed on this core to afford important polycyclic frameworks such as functionalized quinalizinones, pyridinium oxazole dyads (PODs), N-doped polycyclic aromatic hydrocarbons (PAHs), N-doped spiro-PAHs. Additionally, the synthesis of phosphine ligated gold complexes bearing pyrido-isoquinoline scaffold from the pyridino-alkynes will be discussed briefly.

Special Issue: Recent Advances in Transition-Metal Catalysis.

This special issue "Recent Advances in Transition-Metal Catalysis" containing forty-two personal accounts and seven record reviews, discusses the ascendancy of transition metals in modern organic synthesis. The included articles portray the manifold application of transition metals in various processes such as addition/cyclization reactions, asymmetric synthesis, olefin metathesis reactions, coupling reactions, C-H bond activation/functionalization reactions. Additionally, reports describing novel organic transformations based on the employment of transition-metal catalysis in the fields of radical chemistry and materials science are also presented in this collection.

Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii.

BACKGROUND: MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. METHODS: We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. RESULTS: Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. CONCLUSIONS: The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.