Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.308
Filtrar
1.
Chembiochem ; 25(9): e202300837, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38477021

RESUMEN

Dipeptides of a new structure based on ß-triazolalanines and (L)-α-amino acids were synthesized and optimal conditions were developed that ensure both chemical and optical purity of the final products. Molecular docking was carried out and possible intermolecular interactions of dipeptides with potential targets were established. Based on these studies, the analgesic property of chosen dipeptides was studied and it was found that some compounds possess revealed antinociceptive activity in the tail-flick test.


Asunto(s)
Analgésicos , Dipéptidos , Simulación del Acoplamiento Molecular , Triazoles , Analgésicos/química , Analgésicos/farmacología , Analgésicos/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Dipéptidos/química , Dipéptidos/síntesis química , Dipéptidos/farmacología , Animales , Ratones , Masculino
2.
Arch Pharm (Weinheim) ; 357(5): e2300636, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38332463

RESUMEN

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small-molecule dipeptide mimic library to target proteins binding small peptides. The library was created based on the general idea of peptide synthesis, that is, amino acid mimics were reacted in silico to form the dipeptide mimics, yielding 2,036,819 unique compounds. After docking calculations, two compounds from the library were synthesized and tested against WD repeat-containing protein 5 (WDR5) and histamine receptors H1-H4 to evaluate whether these molecules are viable in assays. The compounds showed the highest potency at the histamine H3 receptor, with Ki values in the two-digit micromolar range.


Asunto(s)
Dipéptidos , Bibliotecas de Moléculas Pequeñas , Dipéptidos/química , Dipéptidos/síntesis química , Dipéptidos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Simulación del Acoplamiento Molecular , Humanos , Relación Estructura-Actividad , Receptores Histamínicos/metabolismo , Descubrimiento de Drogas , Estructura Molecular
3.
Molecules ; 27(4)2022 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-35209031

RESUMEN

In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type 5 is presented. These compounds serve as valuable building blocks for the development of highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases. The proposed method is based on the tandem esterification of α-aminophosphinic and acrylic acids under silylating conditions in order to subsequently participate in a P-Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also compatible with the reaction conditions. Based on the above, we expect that the practicality of the proposed protocol will facilitate the discovery of pharmacologically useful bioactive phosphinic peptides.


Asunto(s)
Acrilatos/química , Dipéptidos , Ácidos Fosfínicos/química , Dipéptidos/síntesis química , Dipéptidos/química , Esterificación
4.
Yakugaku Zasshi ; 142(2): 145-153, 2022.
Artículo en Japonés | MEDLINE | ID: mdl-35110451

RESUMEN

The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.


Asunto(s)
Antineoplásicos/síntesis química , Ácidos Borónicos/química , Bortezomib/síntesis química , Desarrollo de Medicamentos/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Inhibidores de Serina Proteinasa/síntesis química , Bortezomib/química , Catálisis , Dipéptidos/síntesis química , Dipéptidos/química , Diseño de Fármacos , Inhibidores de Serina Proteinasa/química , Estereoisomerismo
5.
Chem Res Toxicol ; 34(11): 2366-2374, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34672520

RESUMEN

Emerging evidence has revealed that oxidative damages of DNA correlate with the pathogenesis of some diseases, and numerous investigations have also suggested that supplementation of antioxidants is beneficial for keeping health by rectifying in vivo redox status. Here, we construct antioxidative dipeptides with the Ugi four-component reaction (comprising p-aminobenzyl alcohol, benzaldehyde, or vanillin, a series of antioxidative carboxylic acids and isocyanides as reagents) and then attempt to attach the dipeptides to [60]fullerene by the Bingel reaction. However, this endeavor does not lead to the amelioration of the radical-scavenging property because abilities of fullerenyl dipeptides to trap 2,2'-diphenyl-1-picrylhydrazyl and galvinoxyl radicals are still dependent upon the phenolic hydroxyl group in the dipeptide scaffold rather than upon the fullerenyl group. Alternatively, when the obtained fullerenyl dipeptides are evaluated in a peroxyl radical-induced oxidation of DNA, it is found that introducing a fullerene moiety into dipeptide enables antioxidative effect to be enhanced 20-30% because the fullerene moiety facilitates the corresponding dipeptide to intercalate with DNA strands, and thus, to increase the antioxidative efficacy. Our results suggest that connecting an antioxidative skeleton with the hydrophobic fullerene moiety might lead to a series of novel antioxidant hybrids applied for the inhibition of DNA oxidation.


Asunto(s)
Antioxidantes/farmacología , ADN/antagonistas & inhibidores , Dipéptidos/farmacología , Fulerenos/farmacología , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , ADN/metabolismo , Dipéptidos/síntesis química , Dipéptidos/química , Fulerenos/química , Estructura Molecular , Oxidación-Reducción , Picratos/antagonistas & inhibidores
6.
J Mater Chem B ; 9(41): 8686-8693, 2021 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-34617098

RESUMEN

Short peptides with self-assembled nanostructures are widely applied in the areas of drug delivery systems and biomaterials. In this article, we create a new peptide-based hydrogelator (Fmoc-FFRRVR) based on N-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) through an approach to improve its hydrophilicity. Compared to Fmoc-FF, Fmoc-FFRRVR prefers to form a hydrogel under mild conditions, and the gelation time is only 2 s. Fmoc-FFRRVR self-assembles into organized arrays of ß-sheets in nanofibers via π-stacking of Fmoc-FF, which are supported by circular dichroism and fluorescence emission spectroscopy. Rheology results confirm that the hydrogel of Fmoc-FFRRVR is elastic, reversible and injectable. The newly discovered hydrogel not only retains some excellent performances of Fmoc-FF, but also can be used as a drug carrier for biomedical applications.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Dipéptidos/química , Doxorrubicina/farmacología , Fluorenos/química , Hidrogeles/química , Péptidos/química , Animales , Antibióticos Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dipéptidos/síntesis química , Doxorrubicina/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fluorenos/síntesis química , Humanos , Hidrogeles/síntesis química , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Estructura Molecular , Nanofibras/química , Péptidos/síntesis química
7.
Molecules ; 26(19)2021 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-34641525

RESUMEN

2,5-diketopiperazines (DKPs) are cyclic dipeptides ubiquitously found in nature. In particular, cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) are frequently detected in many microbial cultures. Each of these DKPs has four possible stereoisomers due to the presence of two chirality centers. However, absolute configurations of natural DKPs are often ambiguous due to the lack of a simple, sensitive, and reproducible method for stereochemical assignment. This is an important problem because stereochemistry is a key determinant of biological activity. Here, we report a synthetic DKP library containing all stereoisomers of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro). The library was subjected to spectroscopic characterization using mass spectrometry, NMR, and electronic circular dichroism (ECD). It turned out that ECD can clearly differentiate DKP stereoisomers. Thus, our ECD dataset can serve as a reference for unambiguous stereochemical assignment of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) samples from natural sources. The DKP library was also subjected to a biological screening using assays for E. coli growth and biofilm formation, which revealed distinct biological effects of cyclo(D-Phe-L-Pro).


Asunto(s)
Dipéptidos/química , Péptidos Cíclicos/química , Dicroismo Circular , Dicetopiperazinas/química , Dipéptidos/síntesis química , Dipéptidos/farmacología , Escherichia coli/efectos de los fármacos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Estereoisomerismo , Relación Estructura-Actividad
8.
ACS Appl Mater Interfaces ; 13(37): 44041-44053, 2021 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-34491724

RESUMEN

Treatment of chronic wound infections caused by Gram-positive bacteria such as Staphylococcus aureus is highly challenging due to the low efficacy of existing formulations, thereby leading to drug resistance. Herein, we present the synthesis of a nonimmunogenic cholic acid-glycine-glycine conjugate (A6) that self-assembles into a supramolecular viscoelastic hydrogel (A6 gel) suitable for topical applications. The A6 hydrogel can entrap different antibiotics with high efficacy without compromising its viscoelastic behavior. Activities against different bacterial species using a disc diffusion assay demonstrated the antimicrobial effect of the ciprofloxacin-loaded A6 hydrogel (CPF-Gel). Immune profiling and gene expression studies after the application of the A6 gel to mice confirmed its nonimmunogenic nature to host tissues. We further demonstrated that topical application of CPF-Gel clears S. aureus-mediated wound infections more effectively than clinically used formulations. Therefore, cholic acid-derived hydrogels are an efficacious matrix for topical delivery of antibiotics and should be explored further.


Asunto(s)
Antibacterianos/uso terapéutico , Ciprofloxacina/uso terapéutico , Portadores de Fármacos/química , Hidrogeles/química , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Infección de Heridas/tratamiento farmacológico , Animales , Antibacterianos/química , Ácidos Cólicos/síntesis química , Ácidos Cólicos/química , Ciprofloxacina/química , Dipéptidos/síntesis química , Dipéptidos/química , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Hidrogeles/síntesis química , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Staphylococcus aureus/efectos de los fármacos
9.
J Am Chem Soc ; 143(27): 10374-10381, 2021 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-34191506

RESUMEN

Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.


Asunto(s)
Alquenos/química , Dipéptidos/síntesis química , Oligopéptidos/síntesis química , Catálisis , Dipéptidos/química , Enlace de Hidrógeno , Conformación Proteica
10.
Chem Commun (Camb) ; 57(39): 4839-4842, 2021 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-33870368

RESUMEN

A novel universal N-transfer reagent for direct and effective transformation of α-amino ketones, acetamides, and esters to the corresponding α-diazo products under mild basic conditions has been developed. This one-step synthetic approach not only allows for generation of α-substituted-α-diazo carbonyl compounds from α-amino acid derivatives but also permits preparation of α-diazo dipeptides from N-terminal dipeptides (32 examples, up to 91%).


Asunto(s)
Aminoácidos/química , Compuestos Azo/síntesis química , Compuestos de Diazonio/química , Indicadores y Reactivos/química , Compuestos Azo/química , Dipéptidos/síntesis química , Dipéptidos/química , Estructura Molecular , Sales (Química)/química
11.
Bioorg Med Chem Lett ; 42: 128044, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33865971

RESUMEN

Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA. We hypothesized that substituting the zinc-coordinating urea group for a thiourea group, thus incorporating a sulfur atom, could facilitate stronger binding to zinc(II) within the active site, and thus improve affinity for GCP(II)/PSMA. A structurally analogous urea and thiourea pair (HO-Glu-C(O)-Glu-OH - compound 5 and HO-Glu-C(S)-Glu-OH - compound 6) were synthesized and the inhibitory concentration (IC50) of each compound measured with a cell-based assay, allowing us to refute the hypothesis: the thiourea analogue showed 100-fold weaker binding to PSMA than the urea analogue.


Asunto(s)
Dipéptidos/farmacología , Inhibidores Enzimáticos/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Urea/farmacología , Antígenos de Superficie/metabolismo , Dipéptidos/síntesis química , Dipéptidos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Estructura Molecular , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/química
12.
Appl Radiat Isot ; 173: 109719, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33915408

RESUMEN

Tuberculosis (TB) is a disease caused by Mycobacterium and usually attack the lung. Synthesis of new dipeptide derivatives attached to antitubercular active heterocyclic rings like pyrazine and 1,3,4-oxadiazole called ethyl 2-(2-(5-((pyrazin-2-ylamino) methyl)-1,3,4-oxadiazol-2-ylthio) acetamido) acetamido)-3-(4-hydroxyphenyl) propanoate (EPOGTP) and iodinated EPOGTP are reported. The compounds have been characterized by mass, FT-IR and 1H NMR spectroscopy. Their in vitro investigation against Mycobacterium tuberculosis cell line indicated good IC50value of 210 µg/ml for EPOGTP and 86 µg/ml for iodo-EPOGTP. For study the biodisriution, the direct radioiodination of EPOGTP with iodine-131 using mild oxidizing agent, N-Bromosuccinimide (NBS), was performed and optimized for obtaining the maximum radiochemical purity (97.3 ± 0.47%). Then, the in vivo biodistribution in healthy mice showed good accumulation of radioiodinated EPOGTP in lung of about 41.83 ± 0.23% (the percentage of injected dose per gram of organ) at 15 min post-injection. As a conclusion, the synthetized dipeptide and its iodinated derivative could be further evaluated as a potential antitubercular agents.


Asunto(s)
Antituberculosos/química , Dipéptidos/química , Radioisótopos de Yodo/química , Oxadiazoles/química , Pirazinas/química , Animales , Dipéptidos/síntesis química , Dipéptidos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos
13.
Drug Des Devel Ther ; 15: 1315-1332, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790542

RESUMEN

PURPOSE: The objective of our work was to prepare a potent and safe antimicrobial and anticancer agents, through synthesis of several peptides and examine their biological activities, namely as, cytotoxically potent and antimicrobial and antifungal agents. INTRODUCTION: Multidrug-resistant microbial strains have arisen against all antibiotics in clinical use. Infections caused by these bacteria threaten global public health and are associated with high mortality rates. METHODS: The main backbone structure for the novel synthesized linear peptide is Nα-1, 3-benzenedicarbonyl-bis-(Amino acids)-X, (3-11). A computational docking study against DNA gyrase was performed to formulate a mode of action of the small compounds as antimicrobial agents. RESULTS: The peptide-bearing methionine-ester (4) exhibited potent antimicrobial activity compared to the other synthesized compounds, while, peptide (8), which had methionine-hydrazide fragment was the most potent as antifungal agent against Aspergillus niger with 100% inhibition percent. Compounds (6 and 7) showed the highest potency against breast human tumor cell line "MCF-7" with 95.1% and 79.8% of cell inhibition, respectively. The nine compounds possessed weak to moderate antiproliferative effect over colon tumor cell line. The docking results suggest good fitting through different hydrogen bond interactions with the protein residues. In silico ADMET study also evaluated and suggested that these compounds had promising oral bioavailability features. CONCLUSION: The tested compounds need further modification to have significant antimicrobial and antitumor efficacy compared to the reference drugs.


Asunto(s)
Aminoácidos/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Dipéptidos/farmacología , Simulación del Acoplamiento Molecular , Aminoácidos/síntesis química , Aminoácidos/química , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dipéptidos/síntesis química , Dipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana
14.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671589

RESUMEN

BACKGROUND: Dehydropeptides are analogs of peptides containing at least one conjugate double bond between α,ß-carbon atoms. Its presence provides unique structural properties and reaction centre for chemical modification. In this study, the series of new class of dipeptides containing S-substituted dehydrocysteine with variety of heterocyclic moieties was prepared. The compounds were designed as the building blocks for the construction of artificial metalloenzymes (artzymes). Therefore, the complexing properties of representative compounds were also evaluated. Furthermore, the acknowledged biological activity of natural dehydropeptides was the reason to extend the study for antiproliferative action of against several cancer cell lines. METHODS: The synthetic strategy involves glycyl and phenylalanyl-(Z)-ß-bromodehydroalanine as a substrate in one pot addition/elimination reaction of thiols. After deprotection of N-terminal amino group the compounds with triazole ring were tested as complexones for copper(II) ions using potentiometric titration and spectroscopic techniques (UV-Vis, CD, EPR). Finally, the antiproliferative activity was evaluated by sulforhodamine B assay. RESULTS AND CONCLUSIONS: A simple and efficient procedure for preparation of dipeptides containing S-substituded dehydrocysteine was provided. The peptides containing triazole appeared to be strong complexones of copper(II) ions. Some of the peptides exhibited promising antiproliferative activities against number of cancer cell lines, including cell lines resistant to widely used anticancer agent.


Asunto(s)
Antineoplásicos/farmacología , Dipéptidos/química , Dipéptidos/farmacología , Animales , Antineoplásicos/química , Células 3T3 BALB , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Cisteína/química , Dipéptidos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Enzimas/química , Humanos , Concentración de Iones de Hidrógeno , Ratones , Relación Estructura-Actividad
15.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671801

RESUMEN

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a-which contains morpholine, aniline, and glycylglycinate methyl ester-showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dipéptidos/farmacología , Triazinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dipéptidos/síntesis química , Dipéptidos/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Triazinas/síntesis química , Triazinas/química , Pez Cebra/embriología
16.
Inorg Chem ; 60(5): 2976-2982, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33550804

RESUMEN

Based on the supramolecular interaction between vancomycin (Van), an antibiotic glycopeptide, and D-Ala-D-Ala (DADA) dipeptides, a novel class of artificial metalloenzymes was synthesized and characterized. The presence of an iridium(III) ligand at the N-terminus of DADA allowed the use of the metalloenzyme as a catalyst in the asymmetric transfer hydrogenation of cyclic imines. In particular, the type of link between DADA and the metal-chelating moiety was found to be fundamental for inducing asymmetry in the reaction outcome, as highlighted by both computational studies and catalytic results. Using the [IrCp*(m-I)Cl]Cl ⊂ Van complex in 0.1 M CH3COONa buffer at pH 5, a significant 70% (S) e.e. was obtained in the reduction of quinaldine B.


Asunto(s)
Complejos de Coordinación/química , Dipéptidos/química , Iminas/química , Vancomicina/química , Catálisis , Complejos de Coordinación/síntesis química , Dipéptidos/síntesis química , Hidrogenación , Iridio/química , Oxidación-Reducción , Vancomicina/síntesis química
17.
Bioorg Chem ; 109: 104662, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33626452

RESUMEN

Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (-134.36 kcal mol-1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.


Asunto(s)
Catepsina K/antagonistas & inhibidores , Dipéptidos/farmacología , Oxadiazoles/farmacología , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Dipéptidos/síntesis química , Dipéptidos/química , Diseño de Fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad
18.
J Med Chem ; 64(5): 2534-2575, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33596065

RESUMEN

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody-drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Dipéptidos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inmunoconjugados/farmacología , Proteolisis/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Anticuerpos Monoclonales/inmunología , Antígenos de Neoplasias/inmunología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Dipéptidos/síntesis química , Dipéptidos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Inmunoconjugados/química , Inmunoconjugados/inmunología , Oxidorreductasas/inmunología , Células PC-3 , Factores de Transcripción/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo
19.
J Med Chem ; 64(5): 2576-2607, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33596073

RESUMEN

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Inmunoconjugados/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Dipéptidos/síntesis química , Dipéptidos/farmacocinética , Dipéptidos/uso terapéutico , Femenino , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Inmunoconjugados/inmunología , Inmunoconjugados/farmacocinética , Ratones SCID , Oxidorreductasas/inmunología , Factores de Transcripción/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Amino Acids ; 53(3): 407-415, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33599833

RESUMEN

The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize N-(purin-6-yl)dipeptides containing the terminal fragment of (S)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of N-(purin-6-yl)-(S)-amino acids to dimethyl (S)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of N-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (S,S)- and (R,S)-diastereomers (6:4). Individual (S,S)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of N-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of N-(purin-6-yl)-(S)-alanine as N-(9-benzylpurin-6-yl)-(S)-alanine and N-(7-deazapurin-6-yl)-(S)-alanine. It was found that coupling of these compounds to dimethyl (S)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory Mycobacterium tuberculosis H37Rv strain (MIC 3.1-6.25 µg/mL) were identified.


Asunto(s)
Antibacterianos/síntesis química , Dipéptidos/química , Purinas/química , Aminoácidos/química , Antibacterianos/química , Antibacterianos/farmacología , Dipéptidos/síntesis química , Dipéptidos/farmacología , Estructura Molecular , Estereoisomerismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...