ABSTRACT
An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100-250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).
Subject(s)
Lactams , Microwaves , Lactams/chemistry , Lactams/chemical synthesis , Lactams/pharmacology , Cyclization , Humans , Catalysis , Mice , Animals , Cell Line, Tumor , Acetamides/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacology , Molecular Structure , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistryABSTRACT
BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.
Subject(s)
Cysteine , Electrophoresis, Polyacrylamide Gel , Fluorescent Dyes , Glutathione , Homocysteine , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Cysteine/analysis , Cysteine/chemistry , Glutathione/analysis , Glutathione/chemistry , Homocysteine/analysis , Homocysteine/chemistry , Animals , Photons , Optical Imaging , Arabidopsis/chemistry , Humans , Cyclization , ZebrafishABSTRACT
Herein, we report the functionalization of polyhedral oligosilsesquioxanes (POSS) and related siloxanes with arynes. Using o-triazenylarylboronic acids as aryne precursors and silica gel as the activator, the transformation of siloxane bearing various arynophilic moieties on the side chains was achieved with high yields without touching the siloxane core. This method was applied to the conjugation of POSS and pharmaceutical cores using an aryne derived from the synthetic intermediate of cabozantinib. Furthermore, orthogonal dual functionalization of POSS was realized by combining the aryne reaction with Huisgen cyclization.
Subject(s)
Alkynes , Boronic Acids , Siloxanes , Alkynes/chemistry , Boronic Acids/chemistry , Cyclization , Molecular Structure , Organosilicon Compounds/chemistry , Organosilicon Compounds/chemical synthesis , Siloxanes/chemistry , Triazines/chemistryABSTRACT
An oxidant-free approach to the synthesis of N-glyoxylyl peptides has been developed that utilizes the Lossen rearrangement of the N-terminal glycyl hydroxamic acid residue. The synthesis proceeds via an intramolecular redox mechanism to yield the glyoxylyl peptides, which are then subjected to various peptide cyclization procedures. The reaction scheme is suitable for oxidation-sensitive moieties including amino acids.
Subject(s)
Hydroxamic Acids , Oxidation-Reduction , Peptides , Hydroxamic Acids/chemistry , Hydroxamic Acids/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Molecular Structure , CyclizationABSTRACT
An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.
Subject(s)
Antineoplastic Agents , Carbolines , Rhodium , Rhodium/chemistry , Carbolines/chemistry , Carbolines/chemical synthesis , Carbolines/pharmacology , Catalysis , Cyclization , Molecular Structure , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Stereoisomerism , Humans , Drug Screening Assays, AntitumorABSTRACT
Macrocycles are defined as cyclic compounds with 12 or more members. In medicinal chemistry, they are categorized based on their core chemistry into cyclic peptides and macrocycles. Macrocycles are advantageous because of their structural diversity and ability to achieve high affinity and selectivity towards challenging targets that are often not addressable by conventional small molecules. The potential of macrocyclization to optimize drug-like properties while maintaining adequate bioavailability and permeability has been emphasized as a key innovation in medicinal chemistry. This review provides a detailed case study of the application of macrocyclization over the past 5 years, starting from the initial analysis of acyclic active compounds to optimization of the resulting macrocycles for improved efficacy and drug-like properties. Additionally, it illustrates the strategic value of macrocyclization in contemporary drug discovery efforts.
Subject(s)
Chemistry, Pharmaceutical , Macrocyclic Compounds , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Humans , Cyclization , Drug Discovery , Molecular StructureABSTRACT
We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.
Subject(s)
Antiviral Agents , Cyclopentanes , Guanine , Hepatitis B virus , Cyclopentanes/chemistry , Cyclopentanes/chemical synthesis , Catalysis , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Stereoisomerism , Molecular Structure , Guanine/chemistry , Guanine/analogs & derivatives , Hepatitis B virus/drug effects , Cyclization , Palladium/chemistryABSTRACT
The design of novel 4'-thionucleoside analogues bearing a C2' stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2' center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1',2'-anti thioaminal furnished the desired ß-D-4'-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1',4'-trans isomers, causing a significant decrease in their reaction rate relative to 1',4'-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4'-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.
Subject(s)
Carbon , Cardiac Glycosides , Cyclization , Glycosylation , ThionucleosidesABSTRACT
The trichothecene biosynthesis in Fusarium begins with the cyclization of farnesyl pyrophosphate to trichodiene, followed by subsequent oxygenation to isotrichotriol. This initial bicyclic intermediate is further cyclized to isotrichodermol (ITDmol), a tricyclic precursor with a toxic trichothecene skeleton. Although the first cyclization and subsequent oxygenation are catalyzed by enzymes encoded by Tri5 and Tri4, the second cyclization occurs non-enzymatically. Following ITDmol formation, the enzymes encoded by Tri101, Tri11, Tri3, and Tri1 catalyze 3-O-acetylation, 15-hydroxylation, 15-O-acetylation, and A-ring oxygenation, respectively. In this study, we extensively analyzed the metabolites of the corresponding pathway-blocked mutants of Fusarium graminearum. The disruption of these Tri genes, except Tri3, led to the accumulation of tricyclic trichothecenes as the main products: ITDmol due to Tri101 disruption; a mixture of isotrichodermin (ITD), 7-hydroxyisotrichodermin (7-HIT), and 8-hydroxyisotrichodermin (8-HIT) due to Tri11 disruption; and a mixture of calonectrin and 3-deacetylcalonectrin due to Tri1 disruption. However, the ΔFgtri3 mutant accumulated substantial amounts of bicyclic metabolites, isotrichotriol and trichotriol, in addition to tricyclic 15-deacetylcalonectrin (15-deCAL). The ΔFgtri5ΔFgtri3 double gene disruptant transformed ITD into 7-HIT, 8-HIT, and 15-deCAL. The deletion of FgTri3 and overexpression of Tri6 and Tri10 trichothecene regulatory genes did not result in the accumulation of 15-deCAL in the transgenic strain. Thus, the absence of Tri3p and/or the presence of a small amount of 15-deCAL adversely affected the non-enzymatic second cyclization and C-15 hydroxylation steps.
Subject(s)
Fusarium , Trichothecenes , Fusarium/metabolism , Fusarium/genetics , Cyclization , Trichothecenes/metabolism , Acetylation , Fungal Proteins/metabolism , Fungal Proteins/genetics , Polyisoprenyl Phosphates/metabolism , Biosynthetic PathwaysABSTRACT
Fluorescence imaging is an invaluable tool to study biological processes, and fluorogenic dyes are crucial to enhance cell permeability and target intracellular structures with high specificity. Polymethine dyes are vitally important fluorophores in single-molecule localization microscopy and in vivo imaging, but their use in live cells has been limited by high background fluorescence and low membrane permeability. Here, we present a general strategy to transform polymethine compounds into fluorogenic dyes by implementing a 5-exo-trig ring-closure. This method provides access to bright, fluorogenic polymethine dyes with emissions across the visible and near-infrared spectrum.
Subject(s)
Fluorescent Dyes , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Cyclization , Optical Imaging/methods , Humans , Molecular StructureABSTRACT
Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a strain-promoted reaction is challenging. Here, a reversible, strain-promoted polymerization in cyclic DNA is reported. The use of nonhybridizing, single-stranded spacers as short as a single nucleotide in length can promote DNA cyclization. Molecular strain is generated by duplexing the spacers, leading to ring opening and subsequent polymerization. Then, removal of the strain-generating duplexers triggers depolymerization and cyclic dimer recovery via enthalpy-driven cyclization and entropy-mediated ring contraction. This reversibility is retained even when a protein is conjugated to the DNA strands, and the architecture of the protein assemblies can be modulated between bivalent and polyvalent states. This work underscores the utility of using DNA not only as a programmable ligand for assembly but also as a route to access restorable bonds, thus providing a molecular basis for DNA-based materials with shape-memory, self-healing, and stimuli-responsive properties.
Subject(s)
DNA , Polymerization , DNA/chemistry , Cyclization , Thermodynamics , Nucleic Acid ConformationABSTRACT
A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.
Subject(s)
Antineoplastic Agents , Humans , Molecular Structure , Cyclization , Cell Line, Tumor , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Oxidation-ReductionABSTRACT
Little is known about the structures and catalytic mechanisms of sesterterpene synthases (StTSs), which greatly hinders the structure-based engineering of StTSs for structural diversity expansion of sesterterpenes. We here report on the crystal structures of the terpene cyclization (TC) domains of two fungal StTSs: sesterfisherol synthase (NfSS) and sesterbrasiliatriene synthase (PbSS). Both TC structures contain benzyltriethylammonium chloride (BTAC), pyrophosphate (PPi), and magnesium ions (Mg2+), clearly defining the catalytic active sites. A combination of theory and experiments including carbocationic intermediates modeling, site-directed mutagenesis, and isotope labeling provided detailed insights into the structural basis for their catalytic mechanisms. Structure-based engineering of NfSS and PbSS resulted in the formation of 20 sesterterpenes including 13 new compounds and four pairs of epimers with different configurations at C18. These results expand the structural diversity of sesterterpenes and provide important insights for future synthetic biology research.
Subject(s)
Sesterterpenes , Sesterterpenes/chemistry , Sesterterpenes/metabolism , Cyclization , Terpenes/metabolism , Terpenes/chemistry , Alkyl and Aryl Transferases/metabolism , Alkyl and Aryl Transferases/chemistry , Alkyl and Aryl Transferases/genetics , Protein Engineering , Catalytic Domain , Models, Molecular , Crystallography, X-RayABSTRACT
Enhancing the accumulation and retention of small-molecule probes in tumors is an important way to achieve accurate cancer diagnosis and therapy. Enzyme-stimulated macrocyclization of small molecules possesses great potential for enhanced positron emission tomography (PET) imaging of tumors. Herein, we reported an 18F-labeled radiotracer [18F]AlF-RSM for legumain detection in vivo. The tracer was prepared by a one-step aluminum-fluoride-restrained complexing agent ([18F]AlF-RESCA) method with high radiochemical yield (RCY) (88.35 ± 3.93%) and radiochemical purity (RCP) (>95%). More notably, the tracer can be transformed into a hydrophobic macrocyclic molecule under the joint action of legumain and reductant. Simultaneously, the tracer could target legumain-positive tumors and enhance accumulation and retention in tumors, resulting in the amplification of PET imaging signals. The enhancement of radioactivity enables PET imaging of legumain activity with high specificity. We envision that, by combining this highly efficient 18F-labeled strategy with our intramolecular macrocyclization reaction, a range of radiofluorinated tracers can be designed for tumor PET imaging and early cancer diagnosis in the future.
Subject(s)
Cysteine Endopeptidases , Fluorine Radioisotopes , Positron-Emission Tomography , Positron-Emission Tomography/methods , Fluorine Radioisotopes/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/analysis , Animals , Cyclization , Mice , Humans , Radiopharmaceuticals/chemistry , Cell Line, Tumor , Mice, Inbred BALB C , Fluorides/chemistry , Mice, NudeABSTRACT
Aberrant canonical NF-κB signaling has been implicated in diseases, such as autoimmune disorders and cancer. Direct disruption of the interaction of NEMO and IKKα/ß has been developed as a novel way to inhibit the overactivation of NF-κB. Peptides are a potential solution for disrupting protein-protein interactions (PPIs); however, they typically suffer from poor stability in vivo and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine SNAr chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling in vitro and in vivo, and presented positive metabolic stability, anti-inflammatory effects, and low cytotoxicity. Importantly, our results also revealed that cyclic peptides had huge potential in acute lung injury (ALI) treatment, and confirmed the role of the decafluorobiphenyl-based cyclization strategy in enhancing the biological activity of peptide NEMO-IKKα/ß inhibitors. Moreover, it provided a promising method for the development of peptide-PPI inhibitors.
Subject(s)
Acute Lung Injury , I-kappa B Kinase , Lipopolysaccharides , Peptides, Cyclic , I-kappa B Kinase/metabolism , I-kappa B Kinase/antagonists & inhibitors , Acute Lung Injury/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Animals , Mice , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Humans , NF-kappa B/metabolism , Protein Binding , CyclizationABSTRACT
We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.
Subject(s)
Macrocyclic Compounds , Peptides , Solid-Phase Synthesis Techniques , Sulfides , Sulfides/chemistry , Sulfides/chemical synthesis , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Molecular Structure , CyclizationABSTRACT
Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of α-chiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.
Subject(s)
Amides , Imidazoles , Peptides , Imidazoles/chemistry , Imidazoles/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Amides/chemistry , Cyclization , Stereoisomerism , Molecular StructureABSTRACT
The synthesis and structural revision of the dimerized cyclic hexapeptides antatollamides A (1) and B (2) are reported. These are unique peptides with two proline residues and bicyclic peptides combined by a disulfide bond. Cyclization and disulfide bond formation of the linear peptide led to antatollamide A (1). However, the 1H and 13C NMR spectra of synthetic antatollamide A (1) were not consistent with those of isolated antatollamide A (1). Meanwhile, the NMR spectra of the monomeric cyclic hexapeptide cyclo(Pro-Pro-Phe-dCys-Ile-Val) (3) and the isolated antatollamide A (1) were identified completely. In addition, we found that isolated antatollamide B (2) is cyclo(Pro-Pro-dPhe-dCys-Ile-Val) (4).
Subject(s)
Peptides, Cyclic , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Molecular Structure , Cyclization , DimerizationABSTRACT
The construction of a small molecule library that includes compounds with medium-sized rings is increasingly essential in drug discovery. These compounds are essential for identifying novel therapeutic agents capable of targeting "undruggable" targets through high-throughput and high-content screening, given their structural complexity and diversity. However, synthesizing medium-sized rings presents notable challenges, particularly with direct cyclization methods, due to issues such as transannular strain and reduced degrees of freedom. This review presents an overview of current strategies in synthesizing medium-sized rings, emphasizing innovative approaches like ring-expansion reactions. It highlights the challenges of synthesis and the potential of these compounds to diversify the chemical space for drug discovery, underscoring the importance of medium-sized rings in developing new bioactive compounds.
Subject(s)
Drug Discovery , Manipulation, Osteopathic , Gene Library , CyclizationABSTRACT
Cysteine conjugation is widely used to constrain phage displayed peptides for the selection of cyclic peptides against specific targets. In this study, the nontoxic Bi3+ ion was used as a cysteine conjugation reagent to cross-link peptide libraries without compromising phage infectivity. We constructed a randomized 3-cysteine peptide library and cyclized it with Bi3+, followed by a selection against the maltose-binding protein as a model target. Next-generation sequencing of selection samples revealed the enrichment of peptides containing clear consensus sequences. Chemically synthesized linear and Bi3+ cyclized peptides were used for affinity validation. The cyclized peptide showed a hundred-fold better affinity (0.31 ± 0.04 µM) than the linear form (39 ± 6 µM). Overall, our study proved the feasibility of developing Bi3+ constrained bicyclic peptides against a specific target using phage display, which would potentially accelerate the development of new peptide-bismuth bicycles for therapeutic or diagnostic applications.