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1.
Chemistry ; 30(9): e202303770, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38088462

RESUMO

Thioamides are naturally occurring isosteres of amide bonds in which the chalcogen atom of the carbonyl is changed from oxygen to sulfur. This substitution gives rise to altered nucleophilicity and hydrogen bonding properties with importance for both chemical reactivity and non-covalent interactions. As such, thioamides have been introduced into biologically active compounds to achieve improved target affinity and/or stability towards hydrolytic enzymes but have also been applied as probes of protein and peptide folding and dynamics. Recently, a series of new methods have been developed for the synthesis of thioamides as well as their utilization in peptide chemistry. Further, novel strategies for the incorporation of thioamides into proteins have been developed, enabling both structural and functional studies to be performed. In this Review, we highlight the recent developments in the preparation of thioamides and their applications for peptide modification and study of protein function.


Assuntos
Peptídeos , Tioamidas , Tioamidas/química , Peptídeos/química , Proteínas/química , Amidas , Enxofre
2.
J Am Chem Soc ; 145(47): 25559-25569, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-37968794

RESUMO

Short, synthetic peptides that are displayed by major histocompatibility complex I (MHC I) can stimulate CD8 T cells in vivo to destroy virus-infected or cancer cells. The development of such peptides as vaccines that provide protective immunity, however, is limited by rapid proteolytic degradation. Introduction of unnatural amino acid residues can suppress MHC I antigen proteolysis, but the modified peptides typically display lower affinity for MHC I and/or diminished ability to activate CD8 T cells relative to native antigen. Here, we report a new strategy for modifying MHC I antigens to enhance resistance to proteolysis while preserving MHC I affinity and T cell activation properties. This approach, replacing backbone amide groups with thioamides, was evaluated in two well-characterized antigens presented by HLA-A2, a common human MHC I. For each antigen, singly modified thioamide analogues retained affinity for HLA-A2 and activated T cells specific for the native antigen, as measured via interferon-γ secretion. In each system, we identified a highly potent triply substituted thioamide antigen ("thio-antigen") that displayed substantial resistance to proteolytic cleavage. Collectively, our results suggest that thio-antigens may represent a general and readily accessible source of potent vaccine candidates that resist degradation.


Assuntos
Antígeno HLA-A2 , Tioamidas , Humanos , Tioamidas/farmacologia , Tioamidas/metabolismo , Peptídeos/metabolismo , Linfócitos T CD8-Positivos , Complexo Principal de Histocompatibilidade
3.
Nat Commun ; 14(1): 6050, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770425

RESUMO

Solvent shielding of the amide hydrogen bond donor (NH groups) through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. We demonstrate that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor (>C = O) through a thioamide substitution (>C = S). The membrane permeability is a consequence of the lower desolvation penalty of the macrocycle resulting from a concerted effect of conformational restriction, local desolvation of the thioamide bond, and solvent shielding of the amide NH groups. The enhanced permeability and metabolic stability on thioamidation improve the bioavailability of a macrocyclic peptide composed of hydrophobic amino acids when administered through the oral route in rats. Thioamidation of a bioactive macrocyclic peptide composed of polar amino acids results in analogs with longer duration of action in rats when delivered subcutaneously. These results highlight the potential of O to S substitution as a stable backbone modification in improving the pharmacological properties of peptide macrocycles.


Assuntos
Amidas , Tioamidas , Ratos , Animais , Amidas/química , Tioamidas/química , Disponibilidade Biológica , Peptídeos , Permeabilidade , Aminoácidos , Solventes
4.
Nat Commun ; 14(1): 4626, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37532721

RESUMO

Thioamides are an important, but a largely underexplored class of amide bioisostere in peptides. Replacement of oxoamide units with thioamides in peptide therapeutics is a valuable tactic to improve biological activity and resistance to enzymatic hydrolysis. This tactic, however, has been hampered by insufficient methods to introduce thioamide bonds into peptide or protein backbones in a site-specific and stereo-retentive fashion. In this work, we developed an efficient and mild thioacylation method to react nitroalkanes with amines directly in the presence of elemental sulfur and sodium sulfide to form a diverse range of thioamides in high yields. Notably, this convenient method can be employed for the controlled thioamide coupling of multifunctionalized peptides without epimerization of stereocenters, including the late stage thioacylation of advanced compounds of biological and medicinal interest. Experimental interrogation of postulated mechanisms currently supports the intermediacy of thioacyl species.


Assuntos
Amidas , Tioamidas , Tioamidas/química , Amidas/química , Peptídeos/química , Aminas
5.
J Med Chem ; 66(17): 11893-11904, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37584282

RESUMO

Candida glabrata has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.


Assuntos
Candidíase , Pirazolonas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Antifúngicos/metabolismo , Azóis/farmacologia , Azóis/uso terapêutico , Azóis/metabolismo , Candida glabrata/genética , Candida glabrata/metabolismo , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Proteínas Fúngicas/metabolismo , Pirazolonas/farmacologia , Fatores de Transcrição/metabolismo , Tioamidas
6.
Curr Opin Chem Biol ; 75: 102336, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37269675

RESUMO

Peptides act as biological mediators and play a key role of various physiological activities. Sulfur-containing peptides are widely used in natural products and drug molecules due to their unique biological activity and chemical reactivity of sulfur. Disulfides, thioethers, and thioamides are the most common motifs of sulfur-containing peptides, and they have been extensively studied and developed for synthetic methodology as well as pharmaceutical applications. This review focuses on the illustration of these three motifs in natural products and drugs, as well as the recent advancements in the synthesis of the corresponding core scaffolds.


Assuntos
Produtos Biológicos , Peptídeos , Peptídeos/química , Enxofre , Tioamidas/química , Sulfetos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/química
7.
Cancer Med ; 12(15): 16337-16358, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37387559

RESUMO

INTRODUCTION: Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism-related prognostic model for EC and explore potential targets for cancer treatment. METHOD: Transcriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model. RESULTS: Five glutamine metabolism-related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan-Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high-risk patients whereas immune relevance analysis revealed low immune scores in the high-risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT-503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002). CONCLUSION: Our work established and validated a glutamine metabolism-related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High-risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.


Assuntos
Neoplasias do Endométrio , Glutamina , Terapia de Alvo Molecular , Fosfoglicerato Desidrogenase , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Glutamina/genética , Glutamina/metabolismo , Prognóstico , Humanos , Feminino , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Piperazinas/uso terapêutico , Tioamidas/uso terapêutico , Piridinas/uso terapêutico , Linhagem Celular Tumoral , Animais , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Angew Chem Int Ed Engl ; 62(26): e202303625, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37118109

RESUMO

Thioamide peptides were synthesized in a straightforward one-pot process via the linkage of diverse natural amino acids in the presence of thiolphosphonate and trichlorosilane, wherein carbonyl groups were replaced with thiono compounds with minimal racemization. Experimental and computational mechanistic studies demonstrated that the trichlorosilane enables the activation of carboxylic acids via intense interactions with the Si-O bond, followed by coupling of the carboxylic acids with thiolphosphonate to obtain the key intermediate S-acyl dithiophosphate. Silyl-activated quadrangular metathesis transition states afforded the thioamide peptides. The potential applications of these thioamide peptides were further highlighted via late-stage linkages of diverse natural products and pharmaceutical drugs and the thioamide moiety.


Assuntos
Aminoácidos , Tioamidas , Tioamidas/química , Peptídeos/química , Aminas , Ácidos Carboxílicos
9.
Chem Commun (Camb) ; 59(16): 2283-2286, 2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36735025

RESUMO

Thioamides, thioureas, and thiocarbamates are introduced as stable, sulfur-based metal-binding pharmacophores (MBPs) for use in metalloenzyme fragment-based drug discovery (mFBDD). MBP reactivity, bioactivity, and structural studies show that these molecules can act as ligands for Zn(II)-dependent metalloenzymes including human carbonic anhydrase II (hCAII) and matrix metalloproteinase-2 (MMP-2).


Assuntos
Metaloproteínas , Tioureia , Humanos , Tioamidas , Metaloproteinase 2 da Matriz , Tiocarbamatos/química , Compostos de Sulfidrila , Quelantes
10.
Molecules ; 28(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615533

RESUMO

Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH3-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh3)2] (1), [Ag(mtdzt)(PPh3)3] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO3)]n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(-) bacterial strains, showing high in vitro bioactivity with IC50 values as low as 4.6 µΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC50 values in the range of 3.1-24.0 µΜ, while 3 and 4 maintained the normal fibroblast cells' viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1-4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells' functionalities.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células , Complexos de Coordenação/química , Simulação de Acoplamento Molecular , Prata/química , Tioamidas/farmacologia
11.
Mol Divers ; 27(1): 159-165, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35294672

RESUMO

The reaction of dibenzyl disulfide with various bromine complexes as oxidants and DMSO as solvent can produce thioamides in high yield at 110 °C. Tertiary amines like pyridine and quinoline, which were utilized in this catalyst, are known to generate bromine-addition complexes. The approach is metal- and additive-free, making it a simple and cost-effective way to make a variety of thioamides under favorable circumstances.


Assuntos
Aminas , Quinolinas , Acoplamento Oxidativo , Bromo , Tioamidas , Catálise
12.
Molecules ; 27(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36500368

RESUMO

A convenient protocol was developed for the transformation of N-aryl-substituted benzamides to N-aryl-substituted benzothioamides using N-isopropyldithiocarbamate isopropyl ammonium salt as a novel thiating reagent. The major advantages of this protocol are its one-pot procedure, short reaction times, mild conditions, simple work-up, high yields and pure products.


Assuntos
Amidas , Tioamidas , Indicadores e Reagentes
13.
ACS Appl Bio Mater ; 5(11): 5410-5417, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36251686

RESUMO

This manuscript reports the effect of hydrogen-bonding functionality on the supramolecular assembly of naphthalene-diimide (NDI)-derived amphiphilic building blocks in water. All the molecules contain a central NDI chromophore, functionalized with a hydrophilic oligo-oxyethylene (OE) wedge in one arm and a phenyl group on the opposite arm. They differ by a single H-bonding functionality, which links the NDI chromophore and the phenyl moiety. The H-bonding functionalities are amide, thioamide, urea, and urethane in NDI-A, NDI-TA, NDI-U, and NDI-UT, respectively. All of these molecules exhibit π-stacking in water, as evident from their distinct UV/vis absorption spectra when compared to that of the monomeric dye in THF. However, among these four, only NDI-A and NDI-TA show hydrogelation, while the other two precipitate out of the medium. The NDI-A hydrogel also exhibits transient stability and leads to a crystalline precipitate within ∼5 h. Only NDI-TA produces stable transparent hydrogel with the entangled fibrillar morphology that is typical for gelators. Both NDI-A and NDI-TA showed a thermoresponsive property with a lower critical solution temperature of about 41-42 °C. Powder XRD studies show a parallel orientation for NDI-A and an antiparallel orientation for NDI-TA. Computational studies support this experimental observation and indicate that the NDI-A assembly is highly stabilized by strong H-bonding among the amide groups and π-stacking interaction in the parallel orientation. On the other hand, due to weak H-bonding among the thioamide groups, the binding energy of the parallelly oriented NDI-TA was significantly lower and the optimized structure was disordered. Instead, its antiparallel orientation was more stable, with criss-cross aligned H-bonding interactions and π-π interactions between adjacent aromatic rings. The NDI-TA hydrogel with less ordered OE chains on the surface showed prominent adsorption of serum protein BSA. In sharp contrast, NDI-A did not exhibit any notable interaction with BSA, as evident from the ITC studies.


Assuntos
Hidrogéis , Naftalenos , Adsorção , Naftalenos/química , Hidrogéis/química , Água/química , Tioamidas , Amidas , Hidrogênio
14.
Org Biomol Chem ; 20(44): 8741-8746, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36301138

RESUMO

The treatment of nitro-substituted donor-acceptor cyclopropanes (DACs) with SnCl4 and the subsequent reaction with thioamides provide one-pot access to various thiazole derivatives. Aroylmethylidene malonates were produced as intermediates in the reactions and they underwent conjugate addition followed by cyclocondensation with thioamides to afford the products. This work demonstrates the versatility of this class of cyclopropanes in synthesizing all three 1,3-azoles.


Assuntos
Ciclopropanos , Tioamidas , Tiazóis , Estrutura Molecular , Azóis
15.
Angew Chem Int Ed Engl ; 61(43): e202210367, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36068172

RESUMO

A site-specific method for the preparation of N-glycosylated peptides is described. Incorporation of a peptide backbone thioamide linkage adjacent to an Asp residue facilitates a AgI -promoted, site-specific conversion to N-glycosylated Asn residues in peptides.


Assuntos
Ácido Aspártico , Glicopeptídeos , Ácido Aspártico/metabolismo , Glicopeptídeos/química , Tioamidas , Glicosilação , Peptídeos/metabolismo
16.
Chem Commun (Camb) ; 58(81): 11430-11433, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36134562

RESUMO

A novel thio-Ritter-type reaction of alkyl bromides, nitriles, and hydrogen sulfide has been explored, providing a straightforward approach toward functionally important thioamides. This transformation features a broad substrate scope, operational simplicity, use of available feedstock chemicals, and late-stage functionalizations of bioactive molecules. The reaction mechanism is also proposed.


Assuntos
Sulfeto de Hidrogênio , Tioamidas , Brometos , Estrutura Molecular , Nitrilas/química , Tioamidas/química
17.
Angew Chem Int Ed Engl ; 61(41): e202207521, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35983584

RESUMO

The deshielding or downfield 13 C NMR chemical shift of amide carbonyl carbon upon H-bonding is a widely observed phenomenon. This downfield shift is commonly used as a spectroscopic ruler for H-bonding. However, the very first observation of an upfield 13 C NMR of thiocarbonyl carbon in thioamides upon H-bonding encouraged us to explore the physical origin of the reversal of 13 C NMR chemical shielding. Careful NMR analysis shows that sulfur and selenium-centered H-bonds (S/SeCHBs) induce a shielding effect on the 13 CC=S(Se) while changing from amides to thioamides or selenoamides. In addition, natural chemical shielding (NCS) analysis shows that the σ11 and σ22 components of the isotropic shielding tensor (σ) have a crucial role in this unusual shielding.


Assuntos
Selênio , Carbono , Hidrogênio/química , Ligação de Hidrogênio , Enxofre , Tioamidas
18.
Chem Commun (Camb) ; 58(71): 9950-9953, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35983851

RESUMO

The cis-trans isomerization of (thio)amides was studied by DFT calculations to get the model for the higher preference for the cis conformation by guided predictive chemistry, suggesting how to select the alkyl/aryl substituents on the C/N atoms that lead to the trans isomer. Multilinear analysis, together with cross-validation analysis, helped to select the best fitting parameters to achieve the energy barriers of the cis to trans interconversion, as well as the relative stability between both isomers. Double experimental check led to the synthesis of the best trans candidate with sterically demanding t-butyl substituents, confirming the utility of predictive chemistry, bridging organic and computational chemistry.


Assuntos
Amidas , Tioamidas , Amidas/química , Cinética , Conformação Molecular , Estereoisomerismo
19.
J Org Chem ; 87(18): 12196-12213, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36007261

RESUMO

A novel carbenoid-mediated approach to thioisomünchnones was developed by intermolecular copper-catalyzed reactions of diazoacetamides with aromatic and heteroaromatic thioamides bearing a pyrrolidine moiety. The direction of the reaction can be switched toward 2-amino-2-heteroarylacrylamides by replacing the pyrrolidine with an aniline group or by the use of 2-cyano-2-diazoacetamides. The proposed mechanism and DFT calculations allowed us to rationalize the effect of substituents on the reaction direction. Effective methods were found for the synthesis of previously unknown both 2-heteroarylthioisomünchones and 2-heteroarylacrylamides, based on a wide scope of available reagents with a similar structure. Some of the synthesized thioisomünchnones exhibited multicolor fluorescence in the solid state and solutions.


Assuntos
Cobre , Tioamidas , Acrilamidas , Compostos de Anilina , Catálise , Cobre/química , Estrutura Molecular , Pirrolidinas , Tioamidas/química
20.
Angew Chem Int Ed Engl ; 61(35): e202207346, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35776856

RESUMO

Amide bond replacement with planar isosteric chalcogen analogues has an important implication for the properties of the N-C(X) linkage in structural chemistry, biochemistry and organic synthesis. Herein, we report the first higher chalcogen derivatives of non-planar twisted amides. The synthesis of twisted thioamide in a versatile system has been accomplished by direct thionation without cleavage of the σ N-C bond. The synthesis of twisted selenoamide has been accomplished by selenation with Woollins' reagent. The structures of higher chalcogen analogues of non-planar amides were unambiguously confirmed by X-ray crystallography. Reactivity studies were conducted to determine the effect of isologous N-C(O) to N-C(X) replacement on the properties of the amide linkage. Computational studies were employed to evaluate structural and energetic parameters of amide bond alteration in higher chalcogen amides. The study provides the first experimental evidence on the effect of chalcogen isologues on the structural and electronic properties of the non-planar amide N-C(X) linkage.


Assuntos
Amidas , Calcogênios , Amidas/química , Calcogênios/química , Cristalografia por Raios X , Tioamidas/química
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