Advances In Synthetic Methodologies Research Articles

Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis.

Over the past three decades, DNA-encoded library (DEL) technologies have become one of the most relevant strategies for hit-finding. Recent advances in synthetic methodologies for DNA-encoded libraries rendered the increased chemical space available, but it is unknown how every variety of chemistry affects DNA's integrity. Available assays to quantify DNA damage are restricted to electrophoresis, ligation efficiency, and mostly qPCR quantification and sequencing, which may contain predisposition and inconsistency. We developed an external standard method through LC-MS analysis to accurately quantify DNA damage throughout the chemical transformations. An assessment was conducted on on-DNA chemical reactions that are frequently employed in DEL synthesis, and these results were compared to traditional qPCR measurements. Our study provides a simple, practicable, and accurate measurement for DNA degradation during DEL synthesis. Our finding reveals substantial disagreement among the usual DNA-damaging assessment methods, which have been largely neglected so far.

Advances in the Synthesis of Spirocyclic Nucleosides

AbstractThe nucleosides are the building blocks for nucleic acids and composed of a five-carbon sugar bearing either pyrimidine or purine nucleobase. The biological properties of nucleosides can be tailored by chemically modifying the five-carbon sugar to influence its sugar pucker. The spirocyclic scaffold is an indispensable scaffold in more than ten approved drugs, and its inherent three-dimensionality makes it an ideal modification to influence the sugar pucker and biological properties of nucleosides. However, the introduction of spirocyclic scaffold is often synthetically challenging due to increase in synthetic steps and stereocenters. The present review highlights the advances in synthetic methodologies developed during the past decades for accessing various members of the spiro-functionalized nucleoside family.1 Introduction2 C-1′-Spirocyclic Nucleosides3 C-2′-Spirocyclic Nucleosides4 C-3′-Spirocyclic Nucleosides5 C-4′-Spirocyclic Nucleosides6 Miscellaneous Spirocyclic Nucleosides7 Conclusion and Future Perspectives

Probing the Interaction of NO with C60: Comparison between Endohedral and Exohedral Complexes

Recent advances in synthetic methodologies have opened new strategies for synthesizing stable metal-free electron spin systems based on fullerenes. Introducing nitric oxide (NO) inside a fullerene cage is one of the methods to attain this goal. In the present study, dispersion corrected density functional theory (B3LYP-D3) has been used to evaluate the structure, stability, and electronic properties of NO encapsulated fullerene NO@C60 and compared those with its exohedral fullerene NO.C60 analog. The calculated stabilization energy for NO@C60 is appreciably higher than NO.C60, and this difference is comprehended via the Quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) topological analyses. The delocalization of electron density of NO and the C60 cage in NO@C60 is discussed using electrostatic potential analysis. In addition, an attempt has been made to understand the different locations and orientations involving the interaction of two NO radicals and the fullerene C60. It is shown that the encapsulation of the NO dimer inside the C60 cage is an energetically unfavorable process. On the other hand, stable structures are obtained upon the physisorption of other NO on the surface of NO@C60 and NO.C60. The present work provides an in-depth understanding of the interaction of NO and C60 fullerene, its preferable position, and its orientation in both endohedral and exohedral complexes.

Identification and Biological Evaluation of a Water-Soluble Fullerene Nanomaterial as BTK Kinase Inhibitor.

Thanks to recent advances in synthetic methodology, water-soluble fullerene nanomaterials that interfere with biomolecules, especially DNA/RNA and selected proteins, have been found with tremendous potential for applications in nanomedicine. Herein, we describe the synthesis and evaluation of a water-soluble glycine-derived [60]fullerene hexakisadduct (HDGF) with T h symmetry, which is a first-in-class BTK protein inhibitor. We synthesized and characterized glycine derived [60]fullerene using NMR, ESI-MS, and ATR-FT-IR. DLS and zeta potential were measured and high-resolution transmission electron microscopy (HRTEM) observations were performed. The chemical composition of the water-soluble fullerene nanomaterial was examined by X-ray photoelectron spectrometry. To observe aggregate formation, the cryo-TEM analysis was carried out. The docking studies and molecular dynamic simulations were performed to determine interactions between HDGF and BTK. The in vitro cytotoxicity was evaluated on RAJI and K562 blood cancer cell lines. Subsequently, we examined the induction of cell death by autophagy and apoptosis by determining the expression levels of crucial genes and caspases. We investigated the direct association of HDGF on inhibition of the BTK signalling pathway by examining changes in the calcium levels in RAJI cells after treatment. The inhibitory potential of HDGF against non-receptor tyrosine kinases was evaluated. Finally, we assessed the effects of HDGF and ibrutinib on the expression of the BTK protein and downstream signal transduction in RAJI cells following anti-IgM stimulation. Computational studies revealed that the inhibitory activity of the obtained [60]fullerene derivative is multifaceted: it hampers the BTK active site, interacting directly with the catalytic residues, rendering it inaccessible to phosphorylation, and binds to residues that form the ATP binding pocket. The anticancer activity of produced carbon nanomaterial revealed that it inhibited the BTK protein and its downstream pathways, including PLC and Akt proteins, at the cellular level. The mechanistic studies suggested the formation of autophagosomes (increased gene expression of LC3 and p62) and two caspases (caspase-3 and -9) were responsible for the activation and progression of apoptosis. These data illustrate the potential of fullerene-based BTK protein inhibitors as nanotherapeutics for blood cancer and provide helpful information to support the future development of fullerene nanomaterials as a novel class of enzyme inhibitors.

A Field Guide to Optimizing Peptoid Synthesis.

N-Substituted glycines (peptoids) are a class of peptidomimetic molecules used as materials for health, environmental, and drug delivery applications. Automated solid-phase synthesis is the most widely used approach for preparing polypeptoids, with a range of published protocols and modifications for selected synthetic targets. Simultaneously, emerging solution-phase syntheses are being leveraged to overcome limitations in solid-phase synthesis and access high-molecular weight polypeptoids. This Perspective aims to outline strategies for the optimization of both solid- and solution-phase synthesis, provide technical considerations for robotic synthesizers, and offer an outlook on advances in synthetic methodologies. The solid-phase synthesis sections explore steps for protocol optimization, accessing complex side chains, and adaptation to robotic synthesizers; the sections on solution-phase synthesis cover the selection of initiators, side chain compatibility, and strategies for controlling polymerization efficiency and scale. This text acts as a "field guide" for researchers aiming to leverage the flexibility and adaptability of peptoids in their research.

A review on advances in synthetic methodology and biological profile of spirothiazolidin‐4‐ones

AbstractHeterocycles are important structural components in pharmacophores that are currently being used to treat several diseases. Among the various heterocyclic scaffolds, nitrogen and sulfur containing spiroheterocycles are essential structural motifs that constitute diverse biodynamic agents. In the last two decades, a paradigm shift has occurred in the synthesis of spirothiazolidin‐4‐ones by replacing conventional and multi‐step synthesis with green protocols, that use novel organo and nanocatalysts. In this review, literature on spirothiazolidin‐4‐ones from years 2000–2021 has been summarized into groups of different synthetic strategies and their potential biological activities.

Chemical Modifications of CRISPR RNAs to Improve Gene-Editing Activity and Specificity.

CRISPR (clustered, regularly interspaced, short palindromic repeats) has become a cutting-edge research method and holds great potential to revolutionize biotechnology and medicine. However, like other nucleic acid technologies, CRISPR will greatly benefit from chemical innovation to improve activity and specificity for critical in vivo applications. Chemists have started optimizing various components of the CRISPR system; the present Perspective focuses on chemical modifications of CRISPR RNAs (crRNAs). As with other nucleic acid-based technologies, early efforts focused on well-established sugar and backbone modifications (2'-deoxy, 2'-F, 2'-OMe, and phosphorothioates). Some more significant alterations of crRNAs have been done using bicyclic (locked) riboses and phosphate backbone replacements (phosphonoacetates and amides); however, the range of chemical innovation applied to crRNAs remains limited to modifications that have been successful in RNA interference and antisense technologies. The encouraging results given by these tried-and-true modifications suggest that, going forward, chemists should take a bolder approach─research must aim to investigate what chemistry will have the most impact on maturing CRISPR as therapeutic and other in vivo technologies. With an eye to the future, this Perspective argues that the complexity of CRISPR presents rich unprecedented opportunities for chemists to synergize advances in synthetic methodology and structural biochemistry to rationally optimize crRNA-protein interactions.

Recent Advances in Synthetic Methodologies to Form C-18F Bonds.

Positron emission tomography (PET) is an important technique for the early diagnosis of disease. Due to the specific physical and chemical properties of Fluorine-18, this important isotope is widely used in PET for labelling and molecular imaging, and its introduction into medicine molecules could produce PET tracers. Developing with the development of organic synthetic methodologies, the introduction of Fluorine-18 into drug molecules efficiently and rapidly under mild conditions, and the formation of C-18F chemical bonds, has become one of the leading topics in both organic synthetic chemistry and radiochemistry. In this mini-review, we review a series of recent advances in the organic synthesis of C-18F bonds (2015–2021), including non-catalytic radiofluorinations via good leaving functional groups, transition metal-catalyzed radiofluorinations, and photo- or electro-catalytic synthetic radiofluorinations. As a result of the remarkable advancements in this field, organic synthetic methods for forming C-18F bonds are expected to continue growing.

Simple and Efficient Synthesis of Functionalized Cyclic Carbonate Monomers Using Carbon Dioxide.

Aliphatic polycarbonates represent an important class of materials with diverse applications ranging from battery electrolytes, polyurethane intermediates, and materials for biomedical applications. These materials can be produced via the ring-opening polymerization (ROP) of six- to eight-membered cyclic carbonates derived from precursor 1,3- and 1,5-diols. These diols can contain a range of functional groups depending on the desired thermal, mechanical, and solution properties. Generally, the ring closure to form the cyclic carbonate requires the use of undesirable and hazardous reagents. Advances in synthetic methodologies and catalysis have enabled the use of carbon dioxide (CO2) to perform these transformations with a high conversion of diol to cyclic carbonate, yet modest isolated yields due to oligomerization side reactions. In this Letter, we evaluate a series of bases in the presence of p-toluenesulfonyl chloride and the appropriate diol to better understand their effect on the yield and presence of oligomer byproducts during cyclic carbonate formation from CO2. From this study, N,N-tetramethylethylenediamine (TMEDA) was identified as an optimal base, facilitating the preparation of a diverse array of both six- and eight-membered carbonates from CO2 within 10 to 15 min. The robust conditions for both, the preparation of the diol precursor, and the TMEDA-mediated carbonate synthesis enabled readily telescoping the two-step reaction sequence, greatly simplifying the process of monomer preparation.

Design of Novel Uncharged Organic Superbases: Merging Basicity and Functionality.

ConspectusOne of the constant challenges of synthetic chemistry is the molecular design and synthesis of nonionic, metal-free superbases as chemically stable neutral organic compounds of moderate molecular weight, intrinsically high thermodynamic basicity, adaptable kinetic basicity, and weak or tunable nucleophilicity at their nitrogen, phosphorus, or carbon basicity centers. Such superbases can catalyze numerous reactions, ranging from C-C bond formation to cycloadditions and polymerization, to name just a few. Additional benefits of organic superbases, as opposed to their inorganic counterparts, are their solubility in organic reaction media, mild reaction conditions, and higher selectivity. Approaching such superbasic compounds remains a continuous challenge. However, recent advances in synthetic methodology and theoretical understanding have resulted in new design principles and synthetic strategies toward superbases. Our computational contributions have demonstrated that the gas-phase basicity region of 350 kcal mol-1 and even beyond is easily reachable by organosuperbases. However, despite record-high basicities, the physical limitations of many of these compounds become quickly evident. The typically large molecular weight of these molecules and their sensitivity to ordinary reaction conditions prevent them from being practical, even though their preparation is often not too difficult. Thus, obviously structural limitations with respect to molecular weight and structural complexity must be imposed on the design of new synthetically useful organic superbases, but strategies for increasing their basicity remain important.The contemporary design of novel organic superbases is illustrated by phosphazenyl phosphanes displaying gas-phase basicities (GB) above 300 kcal mol-1 but having molecular weights well below 1000 g·mol-1. This approach is based on a reconsideration of phosphorus(III) compounds, which goes along with increasing their stability in solution. Another example is the preparation of carbodiphosphoranes incorporating pyrrolidine, tetramethylguanidine, or hexamethylphosphazene as a substituent. With gas-phase proton affinities of up to 300 kcal mol-1, they are among the top nonionic carbon bases on the basicity scale. Remarkably, the high basicity of these compounds is achieved at molecular weights of around 600 g·mol-1. Another approach to achieving high basicity through the cooperative effect of multiple intramolecular hydrogen bonding, which increases the stabilization of conjugate acids, has recently been confirmed.This Account focuses on our efforts to produce superbasic molecules that embody many desirable traits, but other groups' approaches will also be discussed. We reveal the crucial structural features of superbases and place them on known basicity scales. We discuss the emerging potential and current limits of their application and give a general outlook into the future.

Light-emitting self-assembled metallacages.

Coordination-driven self-assembly of metallacages has garnered significant interest because of their 3D layout and cavity-cored nature. The well-defined, highly tunable metallacage structures render them particularly attractive for investigating the properties of luminophores, as well as for inducing novel photophysical characters that enable widespread applications. In this review, we summarize the recent advances in synthetic methodologies for light-emitting metallacages, and highlight some representative applications of these metallacages. In particular, we focus on the favorable photophysical properties—including high luminescence efficiency in various physical states, good modularity in photophysical properties and stimulus responsiveness—that have resulted from incorporating ligands displaying aggregation-induced emission (AIE) into metallacages. These features show that the synergy between carrying out coordination-driven self-assembly and using luminophores with novel photophysical characteristics like AIE could stimulate the development of supramolecular luminophores for applications in fields as diverse as sensing, biomedicine and catalysis.

Corrole‐based photodynamic antitumor therapy

AbstractStudy of photodynamic therapy (PDT) based on corroles has become one of the most important topics in corrole chemistry. Advances in synthetic methodology have made it possible for the preparation of structurally diverse corrole photosensitizers. This review covers the recent progress in the study of corrole as a photosensitizer in the photodynamic antitumor therapy. The content is organized in three sections: cellular uptaking and localization of corrole in tumor cells; morphological changes and cytotoxicity after corrole PDT treatment; and the animal level corrole PDT test. The possible mechanism of corrole‐based PDT antitumor activity is also summarized.

Single-Atom Catalysis Using Chromium Embedded in Divacant Graphene for Conversion of Dinitrogen to Ammonia.

Reduction of dinitrogen to ammonia under ambient conditions is a long-standing challenge. The few metal-based catalysts proposed have conspicuous disadvantages such as high cost, high energy consumption, and being hazardous to the environment. Single-atom catalysis has emerged as a new frontier in heterogeneous catalysis and metal atoms atomically dispersed on supports receive more and more attention owing to rapid advances in synthetic methodologies and computational modeling. Herein, we propose metal atoms embedded in divacant graphene as a catalyst for N2 fixation based on density functional calculations. We systematically investigate the potential of using transition metal like Cr, Mn, Fe, Mo and Ru as catalysts and our study reveals that Cr embedded in graphene exhibit good catalytic activity for N2 fixation. The synergy between the metal atoms and graphene surface provides a stable support to the metal center that has a high spin density to promote adsorption of N2 and activation of its N≡N triple bond. Our study deciphers the mechanism of conversion of N2 to ammonia following two possible reaction pathways, distal and enzymatic routes, via sequential protonation and reduction of activated N2 . The study provides a rational framework for conversion of dinitrogen to ammonia using single atom catalyst.

Aminosugar-based immunomodulator lipid A: synthetic approaches.

The immediate immune response to infection by Gram-negative bacteria depends on the structure of a lipopolysaccharide (LPS, also known as endotoxin), a complex glycolipid constituting the outer leaflet of the bacterial outer membrane. Recognition of picomolar quantities of pathogenic LPS by the germ-line encoded Toll-like Receptor 4 (TLR4) complex triggers the intracellular pro-inflammatory signaling cascade leading to the expression of cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The “endotoxic principle” of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A content of LPS comprises a complex mixture of structural homologs varying in the acylation pattern, the length of the (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl long-chain residues and in the phosphorylation status of the β(1→6)-linked diglucosamine backbone. The structural heterogeneity of the lipid A isolates obtained from bacterial cultures as well as possible contamination with other pro-inflammatory bacterial components makes it difficult to obtain unambiguous immunobiological data correlating specific structural features of lipid A with its endotoxic activity. Advanced understanding of the therapeutic significance of the TLR4-mediated modulation of the innate immune signaling and the central role of lipid A in the recognition of LPS by the innate immune system has led to a demand for well-defined materials for biological studies. Since effective synthetic chemistry is a prerequisite for the availability of homogeneous structurally distinct lipid A, the development of divergent and reproducible approaches for the synthesis of various types of lipid A has become a subject of considerable importance. This review focuses on recent advances in synthetic methodologies toward LPS substructures comprising lipid A and describes the synthesis and immunobiological properties of representative lipid A variants corresponding to different bacterial species. The main criteria for the choice of orthogonal protecting groups for hydroxyl and amino functions of synthetically assembled β(1→6)-linked diglucosamine backbone of lipid A which allows for a stepwise introduction of multiple functional groups into the molecule are discussed. Thorough consideration is also given to the synthesis of 1,1′-glycosyl phosphodiesters comprising partial structures of 4-amino-4-deoxy-β-L-arabinose modified Burkholderia lipid A and galactosamine-modified Francisella lipid A. Particular emphasis is put on the stereoselective construction of binary glycosyl phosphodiester fragments connecting the anomeric centers of two aminosugars as well as on the advanced P(III)-phosphorus chemistry behind the assembly of zwitterionic double glycosyl phosphodiesters.

Recent advances in synthetic methodologies for transition metal-free Ullmann condensation reactions

Different methodologies for transition metal-free Ullmann condensation reactions.

Synthesis and Applications of Protein/Peptide-Polymer Conjugates

Recent advances in synthetic methodologies have brought us closer than ever to the precision conferred by nature. For example, the control possible in reversible deactivation radical polymerization enables us to design and synthesize macromolecules with unprecedented control over not only the polymer chain ends, but also the side chain functionality. Furthermore, this functionality can be exploited to afford chemical modification of peptides and proteins, with ever-improving site-specificity, yielding a range of well-defined protein/peptide-hybrid materials. Such materials benefit from the amalgamation of the properties of proteins/peptides with those of the synthetic (macro)molecules in question. Here, the latest developments in the synthesis of functional polymers and their use for preparation of well-defined protein/peptide-polymer conjugates will be discussed, with particular attention focused on modulating the stability, efficacy and/or administration of therapeutic peptides.

ChemInform Abstract: Modern Advances in Heterocyclic Chemistry in Drug Discovery

AbstractReview: [104 refs.

Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp(3) C-H Functionalization.

α-Amino acids (αAA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups on side chains (e.g., serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure αAAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these "conventional" strategies, a strategy based on the selective functionalization of side chain C-H bonds, particularly sp(3) hybridized C-H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs. However, many hurdles related to the low reactivity of C(sp(3))-H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C-H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C-H functionalization reactions for αAA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of αAA substrates, to exert complementary regio- and stereocontrol on C-H functionalization reactions through palladacycle intermediates. A variety of αAA precursors can undergo multiple modes of C(sp(3))-H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the β, γ, and even δ positions to form new αAA products with diverse structures. In addition to transforming αAAs at previously unreachable positions, these palladium-catalyzed C-H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. This approach reduces the synthetic difficulty for many αAAs by bypassing the requirement for stereocontrol at Cα and relies on straightforward and convergent single-bond coupling transformations at the β-methyl position of alanine to access a wide range of β-monosubstituted αAAs. Moreover, these β-monosubstituted αAAs can undergo further C-H functionalization at the β-methylene position to generate various β-branched αAAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging αAAs and may facilitate the efficient total synthesis of complex peptide natural products.

Modern advances in heterocyclic chemistry in drug discovery.

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

Natural Product as a Source of Lead to the Design of New Drugs

Natural products have been a source of medicinal agents since thousands of year and remarkable numbers of modern drugs have been derived from natural sources, predominantly based on their knowledge available in traditional medicine. The modern natural product research is undergoing a revolution due to recent advancements in combinatorial biosynthesis, microbial genomics and screening processes. The total synthesis of complex natural products has long presented a big challenge to the synthetic chemist, and led to considerable advances in synthetic methodology. To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.