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1.
Nat Commun ; 11(1): 4027, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788676

RESUMO

Programmed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tissues that restrict the use of annexins. In this manuscript, we report the rational design of a highly stable fluorogenic peptide (termed Apo-15) that selectively stains apoptotic cells in vitro and in vivo in a calcium-independent manner and under wash-free conditions. Furthermore, using a combination of chemical and biophysical methods, we identify phosphatidylserine as a molecular target of Apo-15. We demonstrate that Apo-15 can be used for the quantification and imaging of drug-induced apoptosis in preclinical mouse models, thus creating opportunities for assessing the in vivo efficacy of anti-inflammatory and anti-cancer therapeutics.


Assuntos
Apoptose , Imageamento Tridimensional , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Feminino , Humanos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Fagocitose/efeitos dos fármacos , Fosfatidilserinas/metabolismo
2.
Molecules ; 25(4)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32093030

RESUMO

As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein-protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.


Assuntos
Desenho de Fármacos , Peptídeos Cíclicos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Células HEK293 , Humanos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
3.
Molecules ; 25(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069902

RESUMO

Antimicrobial resistance to conventional antibiotics and the limited alternatives to combat plant-threatening pathogens are worldwide problems. Antibiotic lipopeptides exert remarkable membrane activity, which usually is not prone to fast resistance formation, and often show organism-type selectivity. Additional modes of action commonly complement the bioactivity profiles of such compounds. The present work describes a multicomponent-based methodology for the synthesis of cyclic polycationic lipopeptides with stabilized helical structures. The protocol comprises an on solid support Ugi-4-component macrocyclization in the presence of a lipidic isocyanide. Circular dichroism was employed to study the influence of both macrocyclization and lipidation on the amphiphilic helical structure in water and micellar media. First bioactivity studies against model phytopathogens demonstrated a positive effect of the lipidation on the antimicrobial activity.


Assuntos
Antifúngicos/química , Lactamas/química , Lipopeptídeos/química , Peptídeos Cíclicos/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Lipopeptídeos/síntese química , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Phytophthora infestans/efeitos dos fármacos
4.
Org Biomol Chem ; 18(15): 2838-2844, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32048704

RESUMO

Naturally occurring cyclic lipopeptides exhibit a diverse range of biological activities and possess several favourable properties. Chemically synthesising and modifying these natural compounds can alter their biological and physical properties. Cyclic lipopeptides are often difficult to synthesise, especially when the lipid moiety is directly attached to the cyclic scaffold. The construction of a series of cyclic lipopeptide analogues of the antifungal peptide iturin A is reported herein. The synthesis of the parent peptide macrocycle was achieved using native chemical ligation (NCL), whereupon the regenerated free thiol was used to attach a lipid moiety using Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology.


Assuntos
Antifúngicos/síntese química , Técnicas de Química Sintética , Peptídeos Cíclicos/síntese química , Compostos de Sulfidrila/química , Antifúngicos/química , Estrutura Molecular , Peptídeos Cíclicos/química
5.
J Med Chem ; 63(7): 3475-3484, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32003561

RESUMO

Tachyplesin I (TPI) is a cationic ß-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Ligação a DNA/farmacologia , Peptídeos Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Proteínas de Bactérias/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Proteínas de Ligação a DNA/síntese química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Peptídeos Cíclicos/síntese química , Estereoisomerismo , Sulfonamidas/farmacologia
6.
J Med Chem ; 63(4): 1576-1596, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32003991

RESUMO

Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.


Assuntos
Catepsina D/antagonistas & inibidores , Catepsina D/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Sítios de Ligação , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Materiais Biomiméticos/toxicidade , Células CACO-2 , Catepsina D/química , Ensaios Enzimáticos , Humanos , Cinética , Estrutura Molecular , Pepstatinas/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/toxicidade , Inibidores de Proteases/síntese química , Inibidores de Proteases/toxicidade , Ligação Proteica , Relação Estrutura-Atividade
7.
Org Biomol Chem ; 18(10): 1851-1876, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32101232

RESUMO

The growing emphasis on macrocycles in engaging difficult therapeutic targets such as protein-protein interactions and GPCRs via preferential adaptation of bioactive and cell penetrating conformations has provided impetus to the search for de novo macrocyclization strategies that are efficient, chemically robust and amenable to diversity creation. An emerging macrocyclization paradigm based on the C-H activation logic, of particular promise in the macrocyclization of complex peptides, has added a new dimension to this pursuit, enabling efficacious access to macrocycles of various sizes and topologies with high atom and step economy. Significant achievements in macrocyclization methodologies and their applications in the synthesis of bioactive natural products and drug-like molecules, employing strategic variations of C-H activation are captured in this review. It is expected that this timely account will foster interest in newer ways of macrocycle construction among practitioners of organic synthesis and chemical biology to advance the field.


Assuntos
Carbono/química , Hidrogênio/química , Peptídeos Cíclicos/síntese química , Técnicas de Química Sintética/métodos , Ciclização
8.
Chem Commun (Camb) ; 56(7): 1082-1084, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894763

RESUMO

G-quadruplexes (G4) are non-canonical nucleic acid structures with important implications in biology. Based on an α-helical fragment of the RHAU helicase that displays high specificity for parallel-stranded G-quadrplexes, herein we demonstrate its head-to-tail cyclization by a high-efficiency ligase. The cyclic peptide exhibits superior stability and binding affinity to a G-quadruplex, and can serve as an excellent investigational tool for chemical biology applications.


Assuntos
RNA Helicases DEAD-box/metabolismo , DNA/metabolismo , Quadruplex G , Fragmentos de Peptídeos/metabolismo , Peptídeos Cíclicos/metabolismo , Células A549 , Ciclização , RNA Helicases DEAD-box/química , DNA/genética , Humanos , Oldenlandia/enzimologia , Fragmentos de Peptídeos/química , Peptídeo Sintases/química , Peptídeos Cíclicos/síntese química , Ligação Proteica , Estabilidade Proteica
9.
Chem Commun (Camb) ; 56(6): 956-959, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31858094

RESUMO

On-resin intramolecular native chemical ligation (NCL) assisted by N-ethylcysteine using Fmoc/SPPS to obtain cyclic peptides is described. N-terminal cysteine-containing peptides were subjected to NCL conditions leading to cyclization-cleavage reactions and consecutive S → N shift, rendering cyclic peptides in good yields and purities. The compounds were evaluated against P. falciparum 3D7.


Assuntos
Peptídeos Cíclicos/síntese química , Compostos de Sulfidrila/química , Cisteína/análogos & derivados , Cisteína/química , Estrutura Molecular , Peptídeos Cíclicos/química , Resinas Sintéticas/química
10.
J Pept Sci ; 26(1): e3225, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31713938

RESUMO

Seven ascidiacyclamide [cyclo(-Ile-oxazoline-d-Val-thiazole-)2 ] (ASC) analogues incorporating the ß-amino acids ßIle, ßoxazoline, and/or d-ßVal were synthesized. We then investigated the effects of the position and number of incorporated ß-amino acids on the structure, cytotoxicity, and copper binding by these seven analogues. The structural analyses revealed that both ßIle and d-ßVal favor a gauche-type θ torsion angles, while ßoxazoline favors a trans-type θ torsion angle. Expansion of the macrocycle by incorporation of ßIle or d-ßVal readily induced molecular folding. On the other hand, the incorporation of two ßoxazoline residues strongly extended the peptide conformation, and the incorporation of one was sufficient for the moderate restriction important for conformational equilibrium and cytotoxicity. Despite expansion of the macrocycles, the structure-cytotoxicity relationships were largely maintained. In studies of complexation of the analogues with Cu (II) ion, the position and number of incorporated ß-amino acids had a large impact on the structure of the metal complex and may contribute to its stabilization.


Assuntos
Aminoácidos/química , Peptídeos Cíclicos/química , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Aminoácidos/síntese química , Dicroísmo Circular , Cobre/química , Peptídeos Cíclicos/síntese química
11.
Med Chem ; 16(3): 358-367, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31161996

RESUMO

BACKGROUND: SIRT5 is one of the seven members (SIRT1-7) of the mammalian sirtuin family of protein acyl-lysine deacylase enzymes. In recent years, important regulatory roles of SIRT5 in (patho)physiological conditions (e.g. metabolism and cancer) have been increasingly demonstrated. For a better biological understanding and therapeutic exploitation of the SIRT5- catalyzed deacylation reaction, more effort on identifying potent and selective SIRT5 inhibitors beyond those currently known would be rewarding. OBJECTIVE: In the current study, we would like to see if it would be possible to develop potent and selective SIRT5 inhibitory lead compounds with a novel structural scaffold than those of the currently known potent and selective SIRT5 inhibitors. METHODS: In the current study, six N-terminus-to-side chain cyclic tripeptides (i.e. 8-13) each harboring the thiourea-type catalytic mechanism-based SIRT5 inhibitory warhead Nε-carboxyethylthiocarbamoyl- lysine as the central residue were designed, synthesized by the Nα-9- fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on the Rink amide 4-methylbenzhydrylamine (MBHA) resin, purified by the semi-preparative reversedphase high performance liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry (HRMS); and were evaluated by the in vitro sirtuin inhibition assay and the in vitro proteolysis assay. RESULTS: Among the cyclic tripeptides 8-13, we found that 10 exhibited a potent (IC50 ~2.2 µM) and selective (≥60-fold over the SIRT1/2/3/6-catalyzed deacylation reactions) inhibition against the SIRT5-catalyzed desuccinylation reaction. Moreover, 10 was found to exhibit a ~42.3-fold stronger SIRT5 inhibition and a greater proteolytic stability than its linear counterpart 14. CONCLUSION: With a novel and modular structural scaffold as compared with those of all the currently reported potent and selective SIRT5 inhibitors, 10 could be also a useful and feasible lead compound for the quest for superior SIRT5 inhibitors as potential chemical/pharmacological probes of SIRT5 and therapeutics for human diseases in which SIRT5 desuccinylase activity is upregulated.


Assuntos
Inibidores de Histona Desacetilases/química , Oligopeptídeos/química , Peptídeos Cíclicos/química , Sirtuínas/antagonistas & inibidores , Tioureia/análogos & derivados , Estabilidade de Medicamentos , Ensaios Enzimáticos , Inibidores de Histona Desacetilases/síntese química , Humanos , Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Pronase/química , Proteólise , Tioureia/síntese química
12.
Org Biomol Chem ; 18(3): 379-390, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31844862

RESUMO

The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of staphylococcus virulence and has been the focus of tremendous interest in the development of effective therapies for pathogenic bacterial infections. With regards to chemotherapeutic based strategies, the significant proportion of currently reported agr-system modulating molecules are mimics of the native ArgC substrate, which is a thioester-based macrocyclic peptide know as the auto-inducing peptide. Over the past two decades, more than two-hundred synthetic analogues have been reported. This review traces the development of the synthetic strategies employed to synthesise these analogues with a particular focus on macrocyclisation. At present these synthetic approaches can be clustered into five broad categories (1) solution-phase cyclisation, (2) immobilised carbodiimide assisted cyclisation, (3) concomitant on-resin cleavage and macrocyclisation, (4) Boc-compatible chemoselective thioesterification, and (5) Fmoc-compatible chemoselective thioesterification. The advantages and limitation provided by each of the approaches are compared and contrasted with a view towards potential reaction scale-up.


Assuntos
Antibacterianos/síntese química , Peptídeos Cíclicos/síntese química , Peptidomiméticos/síntese química , Percepção de Quorum/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Ciclização , Peptídeos Cíclicos/farmacologia , Peptidomiméticos/farmacologia , Proteínas Quinases/química , Staphylococcus/química
13.
Chem Commun (Camb) ; 56(1): 46-49, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31768506

RESUMO

We present the synthesis and transmembrane transport properties of a new family of tris-pyridine-decorated cyclic peptides. These molecules are designed to self-assemble into dimeric shuttles in nonpolar media, which act as symport ionophores in which, apparently, the tris-pyridine scaffold complexes both cations and anions with high potency and efficacy.


Assuntos
Ionóforos/metabolismo , Bicamadas Lipídicas/metabolismo , Peptídeos Cíclicos/metabolismo , Piridinas/metabolismo , Lipossomas Unilamelares/metabolismo , Cálcio/metabolismo , Cloretos/metabolismo , Concentração de Íons de Hidrogênio , Ionóforos/síntese química , Ionóforos/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Piridinas/síntese química , Piridinas/química
14.
J Am Chem Soc ; 141(49): 19193-19197, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31752491

RESUMO

l-Carboranylalanine (LCba) is a unique artificial amino acid containing a cluster of 10 boron atoms. Since the three-dimensional aromaticity and charge distributions of the carborane side chain are quite different from any side chains of proteinogenic amino acids, there is no report whether LCba can be a substrate for the translation machinery. Here, we report studies on the ribosomal incorporation of LCba into peptide via initiation and elongation using the flexizyme-assisted translation system. Our results indicate that only the initiation step could tolerate LCba incorporation, but the elongation steps could not, very likely due to its steric bulkiness of the side chain. Based on this knowledge, we have designed a library of macrocyclic peptides initiated by α-N-(2-choloroacetyl)-l-carboranylalanine (ClAc-LCba) and selected molecules capable of binding to human epidermal growth factor receptor (hEGFR). Two peptides that were forwarded to deeper studies exhibited affinities with KD values at 16 and 20 nM against hEGFR. Computational modeling of one of the peptides suggested that the carborane side chain might be directly involved in the interaction with the hydrophobic ß-sheet core in the EGF binding site of hEGFR, which is consistent with the mutational data where replacing LCba residue with LPhe completely eliminated the binding activity. Cell lines that stably express hEGFR could be stained by incubation with the C-terminal fluorescein-labeled peptides, whereas hEGFR-negative cells could not be stained. This study provides a general strategy for the de novo discovery of carborane-containing macrocyclic peptides targeting various tumor biomarker proteins, potentially applicable to boron neutron capture therapy.


Assuntos
Compostos de Boro/química , Compostos Macrocíclicos/síntese química , Peptídeos Cíclicos/síntese química , Fenilalanina/análogos & derivados , Sítios de Ligação , Terapia por Captura de Nêutron de Boro , Receptores ErbB/química , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Acoplamento Molecular , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Fenilalanina/química , Ligação Proteica , Técnicas de Síntese em Fase Sólida
15.
J Am Chem Soc ; 141(43): 17361-17369, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31577142

RESUMO

Streptide (1) is a peptide-derived macrocyclic natural product that has attracted considerable attention since its discovery in 2015. It contains an unprecedented post-translational modification that intramolecularly links the ß-carbon (C3) of a residue 2 lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered cyclic peptide. Herein, we report the first total synthesis of streptide that confirms the regiochemistry of the lysine-tryptophan cross-link and provides an unambiguous assignment of the stereochemistry (3R vs 3S) of the lysine-2 C3 center. Both the 3R and the originally assigned 3S lysine diastereomers were independently prepared by total synthesis, and it is the former, not the latter, that was found to correlate with the natural product. The approach enlists a powerful Pd(0)-mediated indole annulation for the key macrocyclization of the complex core peptide, utilizes an underdeveloped class of hypervalent iodine(III) aryl substrates in a palladium-catalyzed C-H activation/ß-arylation reaction conducted on a lysine derivative, and provides access to material with which the role of streptide and related natural products may be examined.


Assuntos
Lisina/química , Peptídeos Cíclicos/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Ciclização , Iodo/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Paládio/química , Peptídeos Cíclicos/química , Estereoisomerismo , Triptofano/química
16.
Molecules ; 24(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627265

RESUMO

Grb7 is an adapter protein, overexpressed in HER2+ve breast and other cancers, and identified as a therapeutic target. Grb7 promotes both proliferative and migratory cellular pathways through interaction of its SH2 domain with upstream binding partners including HER2, SHC, and FAK. Here we present the evaluation of a series of monocyclic and bicyclic peptide inhibitors that have been developed to specifically and potently target the Grb7 SH2-domain. All peptides tested were found to inhibit signaling in both ERK and AKT pathways in SKBR-3 and MDA-MB-231 cell lines. Proliferation, migration, and invasion assays revealed, however, that the second-generation bicyclic peptides were not more bioactive than the first generation G7-18NATE peptide, despite their higher in vitro affinity for the target. This was found not to be due to steric hindrance by the cell-permeability tag, as ascertained by ITC, but to differences in the ability of the bicyclic peptides to interact with and penetrate cellular membranes, as determined using SPR and mass spectrometry. These studies reveal that just small differences to amino acid composition can greatly impact the effectiveness of peptide inhibitors to their intracellular target and demonstrate that G7-18NATE remains the most effective peptide inhibitor of Grb7 developed to date.


Assuntos
Antineoplásicos/farmacologia , Células Epiteliais/efeitos dos fármacos , Proteína Adaptadora GRB7/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Peptídeos Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Antineoplásicos/síntese química , Sítios de Ligação , Linhagem Celular , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteína Adaptadora GRB7/genética , Proteína Adaptadora GRB7/metabolismo , Humanos , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Peptídeos Cíclicos/síntese química , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Fosfatidilserinas/química , Fosfatidilserinas/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Relação Estrutura-Atividade , Domínios de Homologia de src/efeitos dos fármacos
17.
Bioorg Med Chem Lett ; 29(22): 126730, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31607609

RESUMO

Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for drug development. In an effort to identify what conformation could be accounting for the bioactive disparity of natural and synthetic cyclic peptides, some structurally-constrained analogs of cyclopeptide Axinastatin 3 were prepared by photo-induced single electron transfer (SET) reaction. Detailed stereochemistry study was performed by experimental electronic circular dichroism combined with theoretical calculations. Our study suggested that the cyclopeptide 1 with ßI-turn presented stronger antitumor activity comparing with those without such secondary structures. Moreover, a rare 'π helix unit' (compound 3) was realized because of the constrained cyclic structure, which could be considered an important research object for future study of unique helix secondary structures.


Assuntos
Peptídeos Cíclicos/farmacologia , Animais , Antineoplásicos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transporte de Elétrons , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Processos Fotoquímicos , Estereoisomerismo , Relação Estrutura-Atividade
18.
Org Lett ; 21(20): 8473-8478, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31596600

RESUMO

A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripotent cyclopropanol precursor. The efficacy of the proposed diversity-oriented approach has been validated by short stereoselective synthesis of natural product chlamydocin, containing a challenging-to-install fragment of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) and a range of its analogues, derivatives of 2-amino-8-oxodecanoic and 2-aminosuberic acids.


Assuntos
Ciclopropanos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ciclopropanos/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Estereoisomerismo
19.
Angew Chem Int Ed Engl ; 58(52): 19073-19080, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31617285

RESUMO

Here, we report a novel "CyClick" strategy for the macrocyclization of peptides that works in an exclusively intramolecular fashion thereby precluding the formation of dimers and oligomers via intermolecular reactions. The CyClick chemistry is highly chemoselective for the N-terminus of the peptide with a C-terminal aldehyde. In this protocol, the peptide conformation internally directs activation of the backbone amide bond and thereby facilitates formation of a stable 4-imidazolidinone-fused cyclic peptide with high diastereoselectivity (>99 %). This method is tolerant to a variety of peptide aldehydes and has been applied for the synthesis of 12- to 23-membered rings with varying amino acid compositions in one pot under mild reaction conditions. The reaction generated peptide macrocycles featuring a 4-imidazolidinone in their scaffolds, which acts as an endocyclic control element that promotes intramolecular hydrogen bonding and leads to macrocycles with conformationally rigid turn structures.


Assuntos
Química Click/métodos , Peptídeos Cíclicos/síntese química
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