RESUMO
Dysregulation in Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is closely linked to various cancer types. The N-terminal domain (NTD) of STAT proteins, upon dimerization, assumes a multifaceted role with remarkable adaptability in mediating interactions between proteins. Consequently, the strategic targeting of the N-terminal domain of STATs has emerged as a promising tactic for disrupting dimerization and impeding the translocation of STAT proteins. In this study, we have deployed an integrated in-silico methodology to rationally design Peptidomimetic foldamers as inhibitors of the N-terminal domains of STAT3 and STAT4, with the objective of disrupting protein dimerization. Consequently, we have judiciously designed a series of peptidomimetics that encompass ß3-amino acids, bearing side chains that mimic the residues within interface II of the dimeric structures of the NTDs. Employing molecular docking techniques; we have assessed the binding affinity of these designed peptidomimetics toward both the NTDs. Furthermore, we have conducted an evaluation of the stability and conformational alterations within the docked complexes over an extensive Molecular Dynamics, subsequently computing the binding free energy utilizing MM/PBSA calculations. Our findings unequivocally demonstrate that the peptidomimetic foldamers we have devised (Peptide-A, Peptide-B, and Peptide-C) exhibit a propensity to bind to and impede the dimerization process of the NTDs of both STAT3 and STAT4. These outcomes serve to underscore the potential of these meticulously designed peptidomimetics as potential candidates meriting further exploration in the realm of cancer prevention and management.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptidomiméticos , Multimerização Proteica , Fator de Transcrição STAT3 , Fator de Transcrição STAT4 , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptidomiméticos/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/química , Multimerização Proteica/efeitos dos fármacos , Humanos , Fator de Transcrição STAT4/metabolismo , Fator de Transcrição STAT4/química , Ligação Proteica , Domínios Proteicos , Desenho de Fármacos , TermodinâmicaRESUMO
The reductive coupling between allylic sulfonylhydrazones and aryl boronic acids gives 1,3-diarylpropene systems with good to excellent yields. Simple reaction conditions, high yields, and good functional group tolerance are the salient features of this reaction which takes place without using any transition-metal catalysts and an inert atmosphere. The substituents on aryl boronic acid or allylic sulfonylhydrazone play a role in the isomerization of the double bond. The 3,3-diphenylacrylaldehyde derived allylic sulfonylhydrazone gives almost exclusively a single isomer.
Assuntos
Ácidos Borônicos , Elementos de Transição , Ácidos Borônicos/química , Estrutura Molecular , Elementos de Transição/química , CatáliseRESUMO
Class-II AP-endonuclease (XthA) and NAD+-dependent DNA ligase (LigA) are involved in initial and terminal stages of bacterial DNA base excision repair (BER), respectively. XthA acts on abasic sites of damaged DNA to create nicks with 3'OH and 5'-deoxyribose phosphate (5'-dRP) moieties. Co-immunoprecipitation using mycobacterial cell-lysate, identified MtbLigA-MtbXthA complex formation. Pull-down experiments using purified wild-type, and domain-deleted MtbLigA mutants show that LigA-XthA interactions are mediated by the BRCT-domain of LigA. Small-Angle-X-ray scattering, 15N/1H-HSQC chemical shift perturbation experiments and mutational analysis identified the BRCT-domain region that interacts with a novel 104DGQPSWSGKP113 motif on XthA for complex-formation. Isothermal-titration calorimetry experiments show that a synthetic peptide with this sequence interacts with MtbLigA and disrupts XthA-LigA interactions. In vitro assays involving DNA substrate and product analogs show that LigA can efficiently reseal 3'OH and 5'dRP DNA termini created by XthA at abasic sites. Assays and SAXS experiments performed in the presence and absence of DNA, show that XthA inhibits LigA by specifically engaging with the latter's BRCT-domain to prevent it from encircling substrate DNA. Overall, the study suggests a coordinating function for XthA whereby it engages initially with LigA to prevent the undesirable consequences of futile cleavage and ligation cycles that might derail bacterial BER.
Assuntos
DNA Ligases/química , DNA Ligases/metabolismo , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Mycobacterium tuberculosis/enzimologia , DNA/química , DNA/metabolismo , Clivagem do DNA , Conformação Proteica , Domínios e Motivos de Interação entre ProteínasRESUMO
A ytterbium triflate-catalyzed diastereoselective [3 + 2] cycloaddition of quinoxalinones with donor-acceptor cyclopropanes and cyclobutanes is described. A series of tetrahydropyrrolo-quinoxalinone derivatives were obtained in high yields (up to 96%) with excellent diastereoselectivities (up to 46:1). Other medicinally important heterocycles like benzoxazinone, isoquinoxalinone, and dibenzoxazepine derivatives were also suitable for the desired annulation reaction. The current method is applicable for the scale-up reaction. Further, the utility of this annulation reaction is demonstrated by the synthesis of densely functionalized proline derivatives.
Assuntos
Ciclopropanos , Quinoxalinas , Catálise , Reação de Cicloadição , Estrutura Molecular , EstereoisomerismoRESUMO
An expeditious method for the synthesis of homo and heterochiral dipeptides containing l-alanine and d/l 2-methyl allo-hydroxyl prolines was developed using direct aminolysis of bicyclic lactones derived from d/l alanine. The impact of C-2 methylation and its spatial orientation on the pyrrolidine ring puckering and prolyl amide bond configuration was ascertained by solution NMR studies. The present studies reveal that C-2 methylation causes the prolyl amide bond to exist exclusively in the trans geometry in both homo- and heterochiral dipeptides. However, the spatial orientation of the C-2 methyl group and its i + 2 position in appropriately capped model dipeptides may nucleate into a turn like structure.
Assuntos
Amidas/química , Dipeptídeos/química , Hidroxiprolina/química , Pirrolidinas/química , Dipeptídeos/síntese química , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Conformação Proteica , EstereoisomerismoRESUMO
Sugar amino acid (SAA)-based foldamers with well-defined secondary structures were appended with N-acetylgalactosamine (GalNAc) sugars to access sequence-defined, multidentate glycoconjugates with full control over number, spacing and position. Conformation analysis of these glycopeptides by extensive NMR spectroscopic studies revealed that the appended GalNAc units had a profound influence on the native conformational behaviour of the SAA foldamers. Whereas the 2,5-cis glycoconjugate showed a helical structure in water, comprising of two consecutive 16-membered hydrogen bonds, its 2,5-trans congener displayed an unprecedented 16/10-mixed turn structure not seen before in any glycopeptide foldamer.
RESUMO
A convergent and flexible strategy for the stereoselective total synthesis of the reported structure of baulamycin A and its congeners has been developed for the first time. Synthetic highlights include a Crimmins aldol reaction to construct the C-1' and C-14 centers, a Crimmins acetate aldol reaction to generate the hydroxy group at the C-13 position, Horner-Wadsworth-Emmons olefination to form the C9-C10 bond, and Evans methylation to install the C-8 center. This synthetic study disclosed that the reported structure of baulamycin A needs to be revised, as its spectroscopic data are not identical with those of the synthetic baulamycin A.
Assuntos
Álcoois Graxos/síntese química , Resorcinóis/síntese química , Álcoois Graxos/química , Estrutura Molecular , Resorcinóis/química , Análise Espectral/métodos , EstereoisomerismoRESUMO
Leishmaniasis, caused by the protozoan parasites of the genus Leishmania, is one of the most neglected diseases endemic in many continents posing enormous global health threats and therefore the discovery of new antileishmanial compounds is of utmost urgency. The antileishmanial activities of a library of sugar amino acid-based linear lipopeptide analogues were examined with the aim to identify potential drug candidates to treat visceral leishmaniasis. It was found that among the synthesized analogues, most of the permethylated compounds exhibited more activity in in vitro studies against intra-macrophagic amastigotes than the non-methylated analogues. SAR and NMR studies revealed that introduction of the N-methyl groups inhibited the formation of any turn structure in these molecules, which led to their improved activities.
Assuntos
Aminoácidos/química , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Lipopeptídeos/síntese química , Lipopeptídeos/farmacologia , Antiprotozoários/química , Técnicas de Química Sintética , Desenho de Fármacos , Leishmania donovani/efeitos dos fármacos , Lipopeptídeos/química , Metilação , Conformação Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-AtividadeRESUMO
Glycosylation of foldamers derived from furanoid sugar amino acids with mannose and a propyltriazole linker results in an unprecedented 16/10 mixed-turn structure in the glycopeptides in water, with a preference for the higher-order structure irrespective of the stereochemistry of the starting foldamer. This is in stark contrast to the structures displayed by the same oligomers in water when mannosylated with a two-carbon-shorter methyltriazole linker: 16-membered turn structure in the cis-foldamer and 10-membered in its trans congener. This demonstrates the defining influence of the linker length on the structural preference of these novel glycopeptide mimics.
Assuntos
Aminoácidos/química , Amino Açúcares/química , Glicopeptídeos/química , Glicosilação , Conformação MolecularRESUMO
Gramicidin S (GS) is a cyclic cationic antimicrobial peptide (CAP) with a wide spectrum of antibiotic activities whose usage has been limited to topical applications owing to its cytotoxic side effects. We have synthesized tetrahydrofuran amino acid (Taa)-containing GS analogues, and we have carried out conformational analysis and explored their structure activity relationships by evaluating their antitubercular, antibacterial and cytotoxic properties. Two of these analogues showed impressive as well as selective activity against Mycobacterium tuberculosis (MTB) without toxicity towards mammalian Vero cells or human RBCs, and are promising as potential leads.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Furanos/química , Furanos/farmacologia , Gramicidina/análogos & derivados , Gramicidina/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Chlorocebus aethiops , Eritrócitos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Células VeroRESUMO
A one pot synthesis of 1H-benzo[g]indoles, tetrahydrobenzo[h]quinolines, and naphtho[1,2-b]azepines from 2-alkynyl benzaldehydes and cyclic amino acids is reported. The salient feature of the strategy involves formation of three new bonds (one C-N and two C-C bonds) by a metal-free decarboxylation/cyclization/one-carbon ring expansion sequence in one pot.
Assuntos
Aminoácidos Cíclicos/química , Azepinas/síntese química , Benzaldeídos/química , Derivados de Benzeno/síntese química , Indóis/síntese química , Quinolinas/síntese química , Alcinos/síntese química , Alcinos/química , Aminoácidos Cíclicos/síntese química , Azepinas/química , Benzaldeídos/síntese química , Derivados de Benzeno/química , Catálise , Técnicas de Química Combinatória , Ciclização , Indóis/química , Quinolinas/químicaRESUMO
We describe a straightforward strategy for the synthesis of strongly fluorescent pyridoindoles by Pd-catalyzed oxidative annulations of internal alkynes with C-3 functionalized indoles through CH/NH bond activation in a one-pot tandem process. Mechanistic investigations reveal the preferential activation of NH indole followed by CH activation during the cyclization process. Photophysical properties of pyridoindoles exhibited the highest fluorescence quantum yield of nearly 80 %, with emission color varying from blue to green to orange depending on the substructures. Quantum mechanical calculations provide insights into the observed photophysical properties. The strong fluorescence of the pyrido[1,2-a]indole derivative has been employed in subcellular imaging, which demonstrates its localization in the cell nucleus.
Assuntos
Indóis/química , Indóis/síntese química , Piridinas/química , Piridinas/síntese química , Catálise , Ciclização , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Estrutura Molecular , Oxirredução , Processos FotoquímicosRESUMO
The BRCA1 carboxyl-terminal (BRCT) domain, an evolutionarily conserved structural motif, is ubiquitous in a multitude of proteins spanning prokaryotic and eukaryotic organisms. In Mycobacterium tuberculosis (Mtb), BRCT domain plays a pivotal role in the catalytic activity of the NAD+-dependent DNA ligase (LigA). LigA is pivotal in DNA replication, catalyzing the formation of phosphodiester bonds in Okazaki fragments and repairing single-strand breaks in damaged DNA, essential for the survival of Mtb. Structural and functional aspects of LigA unveil its character as a highly modular protein, undergoing substantial conformational changes during its catalytic cycle. Although the BRCT domain of Mtb LigA plays an essential role in DNA binding and protein-protein interactions, the precise mechanism of action remains poorly understood. Unravelling the structure of the BRCT domain holds the promise of advancing our understanding of this pivotal domain. Additionally, it will facilitate further exploration of the protein-protein interactions and enhance our understanding of inter domain interactions within LigA, specifically between BRCT and the Adenylation domain. In this study, we demonstrate the overexpression of the BRCT domain of Mtb LigA and conduct its analysis using solution NMR spectroscopy, revealing a well-folded structure and we present the nearly complete chemical shift assignments of both backbone and sidechains. In addition, a secondary structure prediction by TALOS N predicts BRCT consisting of 3 α-helices and 4 ß-sheets, closely resembling the typical structural topology of most BRCT domains.
Assuntos
Mycobacterium tuberculosis , Ressonância Magnética Nuclear Biomolecular , Domínios Proteicos , Estrutura Secundária de Proteína , DNA Ligase Dependente de ATP/química , DNA Ligase Dependente de ATP/metabolismo , DNA Ligases/química , DNA Ligases/metabolismoRESUMO
The first total synthesis of (29S,37S)-malevamide E (1), a potent ion channel inhibitor, has been achieved in a convergent fashion involving Julia-Kocienski olefination, Urpi acetal aldol and Shiina macrolactonization reactions as the key steps. The strategy developed herein is amenable for the synthesis of the other possible isomers in search for the correct stereoisomer of the naturally occurring molecule.
Assuntos
Química Orgânica/métodos , Depsipeptídeos/química , Depsipeptídeos/síntese química , Canais Iônicos/antagonistas & inibidores , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/síntese química , Canais Iônicos/metabolismo , Isomerismo , Espectroscopia de Ressonância Magnética , Peptídeos/síntese química , Peptídeos/química , Sulfonas/síntese química , Sulfonas/químicaRESUMO
Designing cyclic tetrapeptides (CTPs), which fold into desired structures, is often a challenging task. While it is difficult to synthesize them, they are also prone to adopt multiple conformations. In this paper we report the synthesis and conformational studies of CTP mimics, having nonconstrained α(3)ß motif, that exhibit stable ß- and γ-turn structures. We also demonstrate the transformation of ß-turn to γ-turn structure in similar CTPs by inverting the chirality of ß(3) carbon in C-linked-carbo-ß(3)-amino acid (Caa) from R to S.
Assuntos
Aminoácidos/química , Peptídeos Cíclicos/síntese química , Desenho de Fármacos , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Estrutura Secundária de Proteína , Estrutura Terciária de ProteínaRESUMO
We herein report a chemo- and regioselective 6-exo-dig catalytic cyclization of Ugi adducts N-substituted 2-alkynamides to access functionalized morpholinone glycoconjugates in the presence of triphenylphosphine. This array allows an interesting multicomponent access to a library of functionalized morpholinone glycoconjugates under mild reaction conditions with regeneration of catalyst triphenylphosphine, supported by 31P nuclear magnetic resonance studies. Density functional theory shows the 6-exo-dig oxocyclization pathway is preferred, which supports our experimental observation.
RESUMO
The base-promoted intramolecular cyclization of Ugi-azide adduct has been demonstrated for the synthesis of highly substituted aziridinyl glycoconjugates in one pot. The reactions are scalable and efficient and have an operationally simple broad substrate scope. To gain insight into the mechanism of aziridine formation, DFT and control experiments show that the cyclization of the aziridine glycoconjugate pathway was preferred, as it proceeds with a low activation energy barrier (0.57 kcal mol-1), which supports our experimental observation.
RESUMO
A versatile diastereoselective Friedel-Crafts alkylation reaction of heteroaryl systems with a cyclic enecarbamate for the preparation of 5-heteroaryl-substituted proline analogues in good yields has been developed. These heterocyclic tethered cyclic amino acid building blocks constitute important structural motifs in many biologically active molecules. The impact of the substitution on proline cis/trans isomerization was explored by carrying out solution conformational studies by NMR on 5-furanyl-substituted proline-containing peptides. Conformational analysis revealed that the peptide bond is constrained in an exclusively trans conformation.
RESUMO
A new approach to synthesize a homologous series of 14-, 15-, and 16-membered drug-like, macrocyclic glycoconjugates involving TBAHS promoted azide-propenone intramolecular cycloaddition in designed C-glycopyranosyl butenones from a simple sugar d-glucose and d-mannose is reported.