Synthesis of Phenanthrenes and 1-Hydroxyphenanthrenes via Aromatization-Assisted Ring-Closing Metathesis: toward Polynuclear Aromatic Hydrocarbons.

This study presents an efficient synthetic strategy for phenanthrenes and 1-hydroxyphenanthrenes through aromatization-assisted ring-closing metathesis (RCM). It involves vinylation of 1-bromo-2-naphthaldehyde derivatives, Barbier allylation, and subsequent one-pot RCM/dehydration of the diene precursors to yield phenanthrene derivatives. Further, the corresponding keto analogues of diene precursors produce 1-hydroxyphenanthrenes through RCM and aromatization-driven keto-enol tautomerism. This pathway enables rapid access to a diverse array of functionalized phenanthrenes and 1-hydroxyphenanthrenes, including synthetically challenging derivatives containing both -OH and -OMe groups via the sequential construction of the terminal phenanthrene ring.

A non-B DNA binding peptidomimetic channel alters cellular functions.

DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA binding peptide mimic TBP2, which forms transmembrane ion channels, impacting cellular ion concentration and consequently stabilizing G-quadruplex DNA structures. TBP2 self-assembles into nanostructures, e.g., vesicles and nanofibers and facilitates the transportation of Na+ and K+ across lipid membranes with high conductance (~0.6 nS). Moreover, TBP2 exhibits increased fluorescence when incorporated into the membrane or in cellular nuclei. Monomeric TBP2 can enter the lipid membrane and localize to the nuclei of cancer cells. The coordinated process of time-dependent membrane or nuclear localization of TBP2, combined with elevated intracellular cation levels and direct G-quadruplex (G4) interaction, synergistically promotes formation and stability of G4 structures, triggering cancer cell death. This study introduces a platform to mimic and control intricate biological functions, leading to the discovery of innovative therapeutic approaches.

Combating multidrug-resistance in S. pneumoniae: a G-quadruplex binding inhibitor of efflux pump and its bio-orthogonal assembly.

Antibiotic resistance poses a significant global health threat, necessitating innovative strategies to combat multidrug-resistant bacterial infections. Streptococcus pneumoniae, a pathogen responsible for various infections, harbors highly conserved DNA quadruplexes in genes linked to its pathogenesis. In this study, we introduce a novel approach to counter antibiotic resistance by stabilizing G-quadruplex structures within the open reading frames of key resistance-associated genes (pmrA, recD and hsdS). We synthesized An4, a bis-anthracene derivative, using Cu(I)-catalyzed azide-alkyne cycloaddition, which exhibited remarkable binding and stabilization of the G-quadruplex in the pmrA gene responsible for drug efflux. An4 effectively permeated multidrug-resistant S. pneumoniae strains, leading to a substantial 12.5-fold reduction in ciprofloxacin resistance. Furthermore, An4 downregulated pmrA gene expression, enhancing drug retention within bacterial cells. Remarkably, the pmrA G-quadruplex cloned into the pET28a(+) plasmid transformed into Escherichia coli BL21 cells can template Cu-free bio-orthogonal synthesis of An4 from its corresponding alkyne and azide fragments. This study presents a pioneering strategy to combat antibiotic resistance by genetically reducing drug efflux pump expression through G-quadruplex stabilization, offering promising avenues for addressing antibiotic resistance.

Efficient Synthesis of Cyclohepta[b]indoles and Cyclohepta[b]indole-Indoline Conjugates via RCM, Hydrogenation, and Acid-Catalyzed Ring Expansion: A Biomimetic Approach.

Cyclohepta[b]indoles, prevalent in natural products and pharmaceuticals, are conventionally accessed via metal or Lewis acid-mediated cycloadditions with prefunctionalized substrates. Our study introduces an innovative sequential catalytic assembly for synthesizing cyclohepta[b]indoles from readily available isatin derivatives. The process involves three catalytic sequences: ring-closing metathesis, catalytic hydrogenation, and acid-catalyzed ring expansion. The RCM of 2,2-dialkene-3-oxindoles, formed by butenyl Grignard addition to 3-allyl-3-hydroxy-2-oxindoles, yields versatile spirocyclohexene-3-oxindole derivatives. These derivatives undergo further transformations, including dibromination, dihydroxylation, epoxidation, Wacker oxidation at the double bond. Hydrogenation of spirocyclohexene-3-oxindole yields spirocyclohexane-3-oxindoles. Their subsequent acid-catalyzed ring expansion/aromatization, dependent on the acid catalyst, results in either cyclohepta[b]indoles or cyclohepta[b]indole-indoline conjugates, adding a unique synthetic dimension. The utility of this methodology is exemplified through the synthesis of an A-FABP inhibitor, showcasing its potential in pharmaceutical applications.

Selective Recognition of c-KIT 1 G-Quadruplex by Structural Tuning of Heteroaromatic Scaffolds and Side Chains.

In this study, carbazole (MC) and dibenzofuran (MD) derivatives were synthesized to examine their effect on the biomolecular recognition of G-quadruplex (G4) targets. Biophysical studies revealed that MC-4, a carbazole derivative, exhibits a specific affinity and effectively stabilizes the c-KIT 1 G4. Molecular modeling suggests a stable interaction of MC-4 with the terminal G-tetrad of c-KIT 1 G4. Biological studies demonstrate that MC-4 efficiently enters cells, reduces c-KIT gene expression, and induces cell cycle arrest, DNA damage, and apoptosis in cancer cells. These findings demonstrate MC-4 as a selective c-KIT G4 ligand with therapeutic potential, providing insight into the structural basis of its anticancer mechanisms.

Guanosine-based hydrogel as a supramolecular scaffold for template-assisted macrocyclization.

The G-quartet-like supramolecular assembly present in guanosine hydrogel templates macrocyclization between bis-azide and bis-alkyne fragments. The resulting macrocycle enhances viscoelastic properties, and strengthens the hydrogel network. This approach holds potential for the in situ synthesis of drugs and their simultaneous delivery in a stimuli-responsive manner.

pH-dependent complex formation with TAR RNA and DNA: application towards logic gates.

Nucleic acid-based logic gates have shown great potential in biotechnology, medicine as well as diagnostics. Herein, we have constructed pH-responsive logic devices by utilizing HIV-1 TAR hairpins in combination with a thiazole peptide that exhibits turn-on fluorescence upon interacting with TAR RNA or DNA. Based on this, INHIBIT-AND and YES-INHIBIT-AND logic gates were constructed in parallel. The pH alteration leads to conformational changes of the hairpin structure, enabling the construction of a multi-reset reusable logic system which could be developed for in vitro sensing of the HIV-1 viral RNA.

Total Synthesis of Racemic Benzomalvin E, a Quinazolinone Isolated from Pencilium sp. FN070315 and Exploration to the Direct Synthesis of (E)-Benzomalvin B.

We present the first total synthesis of (±) benzomalvin E, featuring a quinazolino moiety with a 6-6-6-7-fused tetracyclic skeleton containing three nitrogen atoms. The key transformation involves Cu-catalyzed intramolecular C-N arylation of quinazolinone, leading to a sclerotigenin analogue that undergoes nucleophilic addition with benzaldehyde, enabling the synthesis of (±) benzomalvin E in six linear steps with a 33% overall yield. The (±) benzomalvin E's structure was validated by 2-D NMR and single crystal XRD analysis and was further transformed into (E)-benzomalvin B.

Potassium tert-Butoxide-Mediated Cascade Synthesis of Rutaecarpine Alkaloid Analogues: Access to Molecular Complexity on Multigram Scales.

In this study, we present a novel and cost-effective approach for synthesizing biologically significant analogues of rutaecarpine alkaloid through a one-step cascade reaction. The pentacyclic core of rutaecarpine alkaloid analogues is efficiently constructed using 2-aminobenzonitriles and substituted indole-2-carbaldehydes in the presence of the affordable base KOtBu. The salient feature of this approach is the promotion of a sequential cascade process within a single reaction vessel including the formation of a dihydroquinazolinone ring, oxidation, and cyclization. This method can be successfully applied on a larger scale, making it economically viable.

Bioorthogonal Chemistry in Translational Research: Advances and Opportunities.

Bioorthogonal chemistry is a rapidly expanding field of research that involves the use of small molecules that can react selectively with biomolecules in living cells and organisms, without causing any harm or interference with native biochemical processes. It has made significant contributions to the field of biology and medicine by enabling selective labeling, imaging, drug targeting, and manipulation of bio-macromolecules in living systems. This approach offers numerous advantages over traditional chemistry-based methods, including high specificity, compatibility with biological systems, and minimal interference with biological processes. In this review, we provide an overview of the recent advancements in bioorthogonal chemistry and their current and potential applications in translational research. We present an update on this innovative chemical approach that has been utilized in cells and living systems during the last five years for biomedical applications. We also highlight the nucleic acid-templated synthesis of small molecules by using bioorthogonal chemistry. Overall, bioorthogonal chemistry provides a powerful toolset for studying and manipulating complex biological systems, and holds great potential for advancing translational research.

Nucleoside-Derived Metallohydrogel Induces Cell Death in Leishmania Parasites.

Self-assembled hydrogels by virtue of their unique 3D network and tunability have extensively been explored for bio-medical applications like tissue engineering, delivery and release of therapeutic agents, etc. Herein, we demonstrate for the first-time nucleoside-based biocompatible hydrogels with a remarkable leishmanicidal effect against both Leishmania major promastigotes and amastigotes and no cytotoxic effect on the macrophage cell line. In this work, a series of biocompatible hydrogels have been synthesized by silver ion-driven self-assembly of natural nucleoside and nucleotide-like cytidine and 5'-GMP. The supramolecular metallogel obtained from the assembly of cytidine and boronic acid is capable of inducing apoptotic-like cell death of protozoan parasite by causing damage to the membrane as well as DNA. These hydrogels could find promising applications in combating cutaneous leishmaniasis by topical treatment.

Nucleic acids as templates and catalysts in chemical reactions: target-guided dynamic combinatorial chemistry and in situ click chemistry and DNA/RNA induced enantioselective reactions.

Nucleic acids play crucial roles in transferring cellular information and gene regulations. DNA and RNA molecules have been associated with multiple human diseases and thus offer opportunities for exploring small molecule-based therapeutics. However, developing target-selective molecules possessing well-defined biological activity, has always been challenging. In the current scenario, where the world is continuously experiencing outbreaks of new infectious diseases, it is always important to expand the scope of chemical toolsets to override conventional drug discovery strategies for developing therapeutically relevant drug candidates. The template-directed synthetic approach has emerged as a promising tool for rapid drug discovery. It allows a biological target to template the selection or synthesis of its ligands from a pool of reactive fragments. There are two main template-directed synthetic strategies: thermodynamically controlled dynamic combinatorial chemistry (DCC) and kinetically controlled target-guided in situ click chemistry. Though discovered only two decades ago, these techniques have proven their usefulness for nucleic acid targets, as exemplified by the increasing number of applications with therapeutically important DNA and RNA targets. However, nucleic acid templated synthetic techniques are relatively unexplored in drug discovery compared to protein targets. In this review article, we have presented a detailed discussion of all the reported nucleic acid templated synthetic studies to portray the great potential of this strategy for efficient hit discovery and lead optimisation. This article would assist in expanding the scope and utility of this strategy through a summary of the advancements and emerging applications. Additionally, a brief overview of the catalytic potential of nucleic acids in asymmetric synthesis has been provided to give a valuable vision of the use of nucleic acids to induce enantioselectivity in chiral drug-like candidates.

Expanding the Toolbox of Target Directed Bio-Orthogonal Synthesis: In Situ Direct Macrocyclization by DNA Templates.

Herein, we demonstrate for the first time that noncanonical DNA can direct macrocyclization-like challenging reactions to synthesize gene modulators. The planar G-quartets present in DNA G-quadruplexes (G4s) provide a size complementary reaction platform for the bio-orthogonal macrocyclization of bifunctional azide and alkyne fragments over oligo- and polymerization. G4s immobilized on gold-coated magnetic nanoparticles have been used as target templates to enable easy identification of a selective peptidomimetic macrocycle. Structurally similar macrocycles have been synthesized to understand their functional role in the modulation of gene function. The innate fluorescence of the in situ formed macrocycle has been utilized to monitor its cellular localization using a G4 antibody and its in cell formation from the corresponding azide and alkyne fragments. The successful execution of in situ macrocyclization in vitro and in cells would open up a new dimension for target-directed therapeutic applications.

Diastereoselective reversible C-C bond exchange of oxindole-thiazolidienediones for dynamic combinatorial chemistry.

We herein describe a diastereoselective aldol exchange involving isatins and thiazolidinediones, providing oxindolyl-thiazolidienediones in aqueous media at pH 6. This equilibrium can also be achieved with oxindole exchange as well as cross-exchange within reasonable timescales. These metal and organic catalyst free reversible reactions provide a unique opportunity for the evolution of dynamic combinatorial libraries (DCLs) for target directed dynamic combinatorial chemistry (DCC) and system chemistry.

Thiazole Containing PNA Mimic Regulates c-MYC Gene Expression through DNA G-Quadruplex.

Peptide nucleic acids (PNAs), besides hybridizing to complementary DNA and RNAs, bind and stabilize DNA secondary structures. Herein, we illustrate the design and synthesis of PNA-like scaffolds by incorporating five-membered thiazole rings as modified bases instead of nucleobases and their subsequent effects on gene regulation by biophysical and in vitro assays. A thiazole-modified PNA trimer selectively recognizes c-MYC G-quadruplex (G4) DNA over other G4s and duplex DNA. It displays a high stabilization potential for the c-MYC G4 DNA and shows remarkable fluorescence enhancement with the c-MYC G4. It is flexible enough to bind at 5' and 3' ends as well as in the groove region of c-MYC G4. Furthermore, the PNA trimer easily permeates the cellular membrane and suppresses c-MYC mRNA expression in HeLa cells by targeting the promoter G4. This study illuminates modified PNAs as flexible molecular tools for selective targeting of noncanonical nucleic acids and modulating gene function.

Cycloaddition of N-sulfonyl and N-sulfamoyl azides with alkynes in aqueous media for the selective synthesis of 1,2,3-triazoles.

The cycloaddition of N-sulfonyl and N-sulfamoyl azides with terminal alkynes generally produces amide derivatives via ketenimine intermediates. We herein delineate a Cu(I) catalyzed method using a prolinamide ligand that selectively generate N-sulfonyl and sulfamoyltriazoles in aqueous media by inhibiting the cleavage of the N1-N2 bond of 5-cuprated triazole intermediates. The present method is mild and tolerant to air, moisture and a wide range of functional groups thereby providing an easy access to a variety of triazole products.

Ring closing metathesis for the construction of carbazole and indole-fused natural products.

The synthesis and functionalization of carbazole ring systems have received considerable attention in organic synthesis due to their widespread occurrence in biologically active compounds. One of the classical methods for the synthesis of carbazoles involves C-C bond formation of a biaryl amine moiety by oxidizing agents. Over the last few years, various new strategies have evolved for the synthesis of carbazole ring systems. During the past two decades, ring-closing metathesis (RCM) based approaches have been efficiently employed for the synthesis of nitrogen containing heteroaromatic systems including carbazoles. Herein, we discuss the construction of carbazole ring systems using RCM and the application of RCM based methods in the preparation of other indole-fused heterocycles. The application of these methods in the synthesis of carbazole alkaloids and bioactive indole-fused natural products has been discussed to highlight the importance of RCM in total synthesis.

Studies Directed towards the Synthesis of the Acridone Family of Natural Products: Total Synthesis of Acronycines and Atalaphyllidines.

A modular and flexible three-step synthetic strategy has been developed for the synthesis of acridone natural products of biological significance. The tetracyclic core of acridone derivatives has been achieved efficiently in high yield from commercially available anthranilic acid and phenol derivatives via condensation reaction, followed by regioselective annulation. Acridone alkaloids acronycine and noracronycine are synthesized in improved overall yields in fewer steps than the previously reported approaches. The method has further been used for the synthesis of atalaphyllidine and 5-hydroxynoracronycine in excellent yields for the first time. Moreover, the synthetic utility of the present strategy has been showcased by the synthesis of oxa and thia analogues of acronycine alkaloid.

Potassium tert-Butoxide Promoted Synthesis of Dihydroquinazolinones.

We herein report an efficient synthetic protocol to access heterocyclic dihydroquinazolinones by a transition-metal-free process, involving the reaction of 2-aminobenzonitriles with aldehydes in the presence of KOtBu. The method is compatible with aromatic ketones providing 2,2-disubstituted dihydroquinazolinones in high yields. This reaction proceeds feasibly at room temperature and features a broad substrate scope and tolerance to a range of functional groups. The mechanism follows a radical pathway.

A [3+2] cycloaddition-1,2-acyl migration-hydrolysis cascade for regioselective synthesis of 1,2,3-triazoles in water.

A cascade sequence involving [3+2] cycloaddition, 1,2-acyl migration and hydrolysis produces 2H-1,2,3-triazoles via the regioselective formation of N2-carboxyalkylated triazoles. The reaction proceeds in aqueous media through intriguing reaction kinetics using a CuI-prolinamide catalyst system. Prolinamide promotes the novel organocatalytic 1,2-acyl migration as well as hydrolysis of the resulting N2-carboxyalkylated triazoles.