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1.
J Biol Chem ; 299(1): 102793, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36509140

RESUMEN

Astrocytic excitatory amino acid transporter 2 (EAAT2) plays a major role in removing the excitatory neurotransmitter L-glutamate (L-Glu) from synaptic clefts in the forebrain to prevent excitotoxicity. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA, 22:6 n-3) enhance synaptic transmission, and their target molecules include EAATs. Here, we aimed to investigate the effect of DHA on EAAT2 and identify the key amino acid for DHA/EAAT2 interaction by electrophysiological recording of L-Glu-induced current in Xenopus oocytes transfected with EAATs, their chimeras, and single mutants. DHA transiently increased the amplitude of EAAT2 but tended to decrease that of excitatory amino acid transporter subtype 1 (EAAT1), another astrocytic EAAT. Single mutation of leucine (Leu) 434 to alanine (Ala) completely suppressed the augmentation by DHA, while mutation of EAAT1 Ala 435 (corresponding to EAAT2 Leu434) to Leu changed the effect from suppression to augmentation. Other polyunsaturated fatty acids (docosapentaenoic acid, eicosapentaenoic acid, arachidonic acid, and α-linolenic acid) similarly augmented the EAAT2 current and suppressed the EAAT1 current. Finally, our docking analysis suggested the most stable docking site is the lipid crevice of EAAT2, in close proximity to the L-Glu and sodium binding sites, suggesting that the DHA/Leu434 interaction might affect the elevator-like slide and/or the shapes of the other binding sites. Collectively, our results highlight a key molecular detail in the DHA-induced regulation of synaptic transmission involving EAATs.


Asunto(s)
Ácidos Docosahexaenoicos , Transportador 2 de Aminoácidos Excitadores , Transmisión Sináptica , Xenopus laevis , Ácidos Docosahexaenoicos/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ácido Glutámico/metabolismo , Leucina , Mutación , Xenopus laevis/metabolismo
2.
Chemistry ; 30(5): e202303393, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-37984364

RESUMEN

Here we show that the sp-hybridized nitrogen cation is strongly stabilized by a peri-iodine substituent in the tetralone system. The cation is captured by anionic species such as CF3 CO2 - , affording hypervalent iodine(III) compounds with a short nitrogen-iodine (N-I) bond, in which the cation serves as a Lewis acid. Notably, the O-I bond of the O-trifluoroacetate or O-acetate is intrinsically weaker than the N-I bond due to its more ionic character and is further weakened by protonation in trifluoroacetic acid. As a result, the oxygen ligand can dissociate in the presence of a Brønsted acid, affording a I+ cation intermediate that retains the N-I bond. We isolated the cation as the tetrafluoroborate, and characterized it experimentally by 1 H NMR spectroscopy and X-ray structure analysis, and theoretically by means of DFT calculation. The results suggest that the N-I bonded cation is intrinsically stable, and is weakly coordinated with water and the BF4 counter anion or trifluoroacetate anion. This cation can be employed as a reagent for α-oxidation of ketones.

3.
Bioorg Chem ; 145: 107220, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38387401

RESUMEN

In this study, we explored the potential of the photoremovable o-nitrobenzyl (oNB) group as a tool to manipulate the membrane permeability and regulate the conformation of linear peptides by means of experimental and computational studies. We found that the introduction of one or more oNB groups markedly increased the permeability and altered the conformation, as compared to the corresponding unmodified peptides. We thoroughly investigated the impact of peptide length, number of oNB group, oNB insertion position, and introduction of N- and C-terminal protecting groups on the passive membrane permeability by means of parallel artificial membrane permeability assay (PAMPA). Photoreaction of peptides containing one or two oNB groups proceeded cleanly in moderate to high yields, releasing the unprotected parent linear peptide. The oNB-modified peptides showed a cis/trans conformational equilibrium, while after photolysis, the unprotected linear peptides showed only the trans-amide conformation. Furthermore, a comprehensive comparison of oNB-modified peptides and N-methylated peptides was conducted, encompassing conformational analysis and physicochemical properties. N-Substituted peptides favored a folded-like structure, which may contribute to the improvement in permeability.


Asunto(s)
Membranas Artificiales , Péptidos , Péptidos/química , Permeabilidad de la Membrana Celular , Conformación Molecular , Permeabilidad
4.
Nature ; 548(7667): 356-360, 2017 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-28792932

RESUMEN

Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.


Asunto(s)
Lisofosfolípidos/química , Lisofosfolípidos/metabolismo , Receptores del Ácido Lisofosfatídico/química , Receptores del Ácido Lisofosfatídico/metabolismo , Alopecia/congénito , Alopecia/genética , Animales , Sitios de Unión , Membrana Celular/metabolismo , Cristalografía por Rayos X , Células HEK293 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Mutagénesis , Filogenia , Estabilidad Proteica , Estructura Secundaria de Proteína , Receptores del Ácido Lisofosfatídico/genética , Especificidad por Sustrato , Pez Cebra/genética
5.
Chem Pharm Bull (Tokyo) ; 71(7): 584-615, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37394607

RESUMEN

Our group has reported various derivatives of lysophosphatidylserine (LysoPS) as potent and subtype-selective agonists for G-protein-coupled receptors (GPCRs). However, the ester linkage between the glycerol moiety and fatty acid or fatty acid surrogate is present in all of them. In order to develop these LysoPS analogs as drug candidates, appropriate pharmacokinetic consideration is essential. Here, we found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood. Accordingly, we examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability in vitro.


Asunto(s)
Lisofosfolípidos , Receptores Acoplados a Proteínas G , Ratones , Animales , Receptores Lisofosfolípidos/agonistas , Receptores Lisofosfolípidos/metabolismo , Lisofosfolípidos/química , Lisofosfolípidos/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Ácidos Grasos/metabolismo , Glicerol/química
6.
J Org Chem ; 87(22): 15224-15249, 2022 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-36318089

RESUMEN

The amino group in aminocarboxylic acids is sufficiently basic to be protonated in strong acids, and consequently, ionization of the carboxylic acid to an acylium ion is blocked due to charge-charge repulsion. Thus, acylation of aromatic compounds is significantly retarded in Friedel-Craft type reactions. We found that Friedel-Crafts acylation with aminocarboxylic acids can proceed smoothly even in a strong Brønsted acid (triflic acid, TfOH) if the Lewis base P4O10 is added. Here we describe the Friedel-Crafts acylation reactions of anthranilic acid and α- to δ-aminocarboxylic acids with benzene derivatives in the presence of P4O10. Non-amino-containing carboxylic acids as well as N-containing heteroaromatic carboxylic acids are available, and α-amino acids can be directly utilized without any protective group. Most substrates afford acylation products in high yields, although some epimerization/racemization may occur. Density functional theory (DFT) calculations suggested that P4O10 neutralizes the protonated amine, converting the N-H covalent bond to a N-hydrogen bond and allowing the carboxylic acid OH functionality to serve as a good leaving group.


Asunto(s)
Ácidos , Bases de Lewis , Acilación , Ácidos Carboxílicos , Enlace de Hidrógeno
7.
J Org Chem ; 87(19): 12653-12672, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-36083501

RESUMEN

Neighboring group participation involving a 6-membered ring structure is rare, despite the privilege of 6-membered ring transition structures in organic chemistry. We examined the putative role of a 6-membered cyclic intermediate with neighboring group participation of nitrogen cation in syn-migration of peri-ester indanone oximes. Direct observation of a peri-methyl ester-iminylium intermediate in solution by means of 1H NMR supported the existence of the 6-membered cation intermediate. Density functional theory (DFT) calculations also supported the intervention of this intermediate in the rearrangement and indicated that it has a planar structure stabilized by electron delocalization.


Asunto(s)
Nitrógeno , Oximas , Cationes , Ésteres , Indanos , Nitrógeno/química , Oximas/química
8.
J Org Chem ; 87(3): 1641-1660, 2022 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-34082529

RESUMEN

We studied the Z/E preference of N-phenylthioacetamide (thioacetanilide) derivatives in various solvents by means of 1H NMR spectroscopy, as well as molecular dynamics (MD) and other computational analyses. Our experimental results indicate that the Z/E isomer preference of secondary (NH)thioamides of N-phenylthioacetamides shows substantial solvent dependency, whereas the corresponding amides do not show solvent dependency of the Z/E isomer ratios. Detailed study of the solvent effects based on molecular dynamics simulations revealed that there are two main modes of hydrogen (H)-bond formation between solvent and (NH)thioacetamide, which influence the Z/E isomer preference of (NH)thioamides. DFT calculations of NH-thioamide in the presence of one or two explicit solvent molecules in the continuum solvent model can effectively mimic the solvation by multiple solvent molecules surrounding the thioamide in MD simulations and shed light on the precise nature of the interactions between thioamide and solvent. Orbital interaction analysis showed that, counterintuitively, the Z/E preference of NH-thioacetamides is mainly determined by steric repulsion, while that of sterically congested N-methylthioacetamides is mainly determined by thioamide conjugation.


Asunto(s)
Simulación de Dinámica Molecular , Tioamidas , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Solventes/química , Tioamidas/química
9.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-36555475

RESUMEN

Epidermal growth factor receptor (EGFR) resistance to tyrosine kinase inhibitors can cause low survival rates in mutation-positive non-small cell lung cancer patients. It is necessary to predict new mutations in the development of more potent EGFR inhibitors since classical and rare mutations observed were known to affect the effectiveness of the therapy. Therefore, this research aimed to perform alanine mutagenesis scanning on ATP binding site residues without COSMIC data, followed by molecular dynamic simulations to determine their molecular interactions with ATP and erlotinib compared to wild-type complexes. Based on the result, eight mutations were found to cause changes in the binding energy of the ATP analogue to become more negative. These included G779A, Q791A, L792A, R841A, N842A, V843A, I853A, and D855A, which were predicted to enhance the affinity of ATP and reduce the binding ability of inhibitors with the same interaction site. Erlotinib showed more positive energy among G779A, Q791A, I853A, and D855A, due to their weaker binding energy than ATP. These four mutations could be anticipated in the development of the next inhibitor to overcome the incidence of resistance in lung cancer patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Humanos , Adenosina Trifosfato , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/farmacología
10.
Molecules ; 27(18)2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36144714

RESUMEN

In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic species involved are isocyanate cation and acylium cation, respectively, and both have a common +C=O structure, which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However, aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion. Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame the superelectrophilic character.


Asunto(s)
Compuestos de Amonio , Bases de Lewis , Ácidos , Acilación , Carbamatos , Ácidos Carboxílicos , Cationes/química , Isocianatos/química , Estructura Molecular , Organofosfatos , Salicilatos
11.
Molecules ; 27(3)2022 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-35164092

RESUMEN

Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Conformación Proteica/efectos de los fármacos
12.
Chem Pharm Bull (Tokyo) ; 69(7): 681-692, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33952867

RESUMEN

Protein-protein interactions (PPIs) are often mediated by helical, strand and/or coil secondary structures at the interface regions. We previously showed that non-naturally occurring, stable helical trimers of bicyclic ß-amino acids (Abh) with all-trans amide bonds can block the p53-MDM2/MDMX α-helix-helix interaction, which plays a role in regulating p53 function. Here, we conducted docking and molecular dynamics calculations to guide the structural optimization of our reported compounds, focusing on modifications of the C-terminal/N-terminal residues. We confirmed that the modified peptides directly bind to MDM2 by means of thermal shift assay, isothermal titration calorimetry, and enzyme-linked immunosorbent assay (ELISA) experiments. Biological activity assay in human osteosarcoma cell line SJSA-1, which has wild-type p53 and amplification of the Mdm2 gene, indicated that these peptides are membrane-permeable p53-MDM2/MDMX interaction antagonists that can rescue p53 function in the cells.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Oligopéptidos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Conformación de Carbohidratos , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Oligopéptidos/química , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo
13.
Biochemistry ; 59(11): 1173-1201, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32124599

RESUMEN

When lipid mediators bind to G-protein-coupled receptors (GPCRs), the ligand first enters the lipid bilayer, then diffuses laterally in the cell membrane to make hydrophobic contact with the receptor protein, and finally enters the receptor's binding pocket. In this process, the location of the hydrophobic contact point on the surface of the receptor has been little discussed even in cases in which the crystal structure has been determined, because the ligand binding pocket is buried inside the transmembrane (TM) domains. Here, we coupled an activator ligand to a series of membrane phospholipid surrogates, which constrain the depth of entry of the ligand into the lipid bilayer. Consequently, via measurement of the receptor-activating activity as a function of the depth of entry into the membrane, these surrogates can be used as molecular rulers to estimate the location of the hydrophobic contact point on the surface of GPCR. We focused on lysophosphatidylserine (LysoPS) receptor GPR34 and prepared a series of simplified membrane-lipid-surrogate-conjugated lysophospholipid analogues by attaching alkoxy amine chains of varying lengths to the hydrophobic tail of a potent GPR34 agonist. As expected, the activity of these lipid-conjugated LysoPS analogues was dependent on chain length. The predicted contact position matches the position of the terminal benzene ring of a nonlipidic ligand that protrudes between TMs 4 and 5 of the receptor. We further found that the nature of the terminal hydrophilic functional group of the conjugated membrane lipid surrogate strongly influences the activity, suggesting that lateral hydrophilic contact of LysoPS analogues with the receptor's surface is also crucial for ligand-GPCR binding.


Asunto(s)
Membrana Celular/metabolismo , Lisofosfolípidos/metabolismo , Receptores Lisofosfolípidos/metabolismo , Secuencias de Aminoácidos , Membrana Celular/química , Membrana Celular/genética , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Lisofosfolípidos/química , Unión Proteica , Dominios Proteicos , Receptores Lisofosfolípidos/química , Receptores Lisofosfolípidos/genética
14.
J Org Chem ; 85(2): 876-901, 2020 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-31800245

RESUMEN

Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R1R2N+═C═O) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- and nine-membered benzolactams.

15.
Chirality ; 32(6): 790-807, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32239582

RESUMEN

Bridged bicyclic amino acids have high potential applicability as self-organized, conformationally constrained synthetic building blocks that do not require assistance from hydrogen bond formation. We systematically investigated the intrinsic conformational propensities of dipeptides of bridged bicyclic ß-amino acids by means of accelerated molecular dynamics simulation and density functional theory (DFT) calculations in methanol, chloroform, and water. While the main-chain conformation, represented by φ and θ values, is fixed by the nature of the bicyclic ring structure, rotation of the C-terminal carbonyl group (ψ) is also restricted, converging to one or two minima. In endo-type dipeptides, in which the two N- and C-terminal amides are spatially close to each other, the C-terminal amide plane is placed horizontally. In exo-type dipeptides, in which the two amides are on opposite sides of the ring plane, the C-terminal carbonyl group can take two types of positions: either parallel/antiparallel with the N-terminal carbonyl or beneath the bicyclic ring, forcing the amide NHMe moiety to lie outside of the ring. We also examined the cis-trans preference of model bicyclic amides. Although the parent amides exhibit cis-trans equilibrium without any preference, addition of a methyl group on one of the bridgehead positions tips the equilibrium towards trans.


Asunto(s)
Aminoácidos/química , Dipéptidos/química , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Estereoisomerismo
16.
Angew Chem Int Ed Engl ; 59(10): 3988-3993, 2020 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-31886618

RESUMEN

C-S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C-S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C-N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol-substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur-containing thio-indolactam V, in addition to an unusual indole-fused 6/5/8-tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio-indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Toxinas de Lyngbya/biosíntesis , Biocatálisis , Cristalografía por Rayos X , Sistema Enzimático del Citocromo P-450/química , Toxinas de Lyngbya/química , Conformación Molecular , Simulación de Dinámica Molecular , Pseudomonas putida/enzimología , Especificidad por Sustrato
18.
Chem Pharm Bull (Tokyo) ; 67(10): 1139-1143, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31582633

RESUMEN

We have discovered that ß-amino acid homooligomers with cis- or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike α-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are autogenous conformations that are stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. A structural overlap comparison of helical cis/trans bicyclic ß-proline homooligomers with typical α-helix structure of α-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridgehead substituents of the present homooligomers point outwards from the helical surface. We were interested to know whether such non-naturally occurring divergent helical molecules could mimic α-helix structures. In this study, we show that bicyclic ß-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.


Asunto(s)
Proteínas Nucleares/química , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas/química , Proteína p53 Supresora de Tumor/química , Proteínas de Ciclo Celular , Humanos , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Prolina/análogos & derivados , Prolina/farmacología , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
19.
J Org Chem ; 83(1): 203-219, 2018 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-29189006

RESUMEN

The mechanisms of intramolecular cyclization of 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanones (1) under basic (DABCO and t-BuOK) and acidic (AcOH and TFA) conditions were investigated by means of experimental and computational methods. The ketone, enol, and enolate forms of 1 can afford different intramolecular cyclization products (2, 3, 4), depending on the conditions. The results of the reaction of 1 under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (t-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketones, which exhibit reactivities arising from both the oxygen lone-pair electrons (O atom reactivity) and carbon σ-electrons (C atom reactivity). The neutral enol in DABCO afforded 2H-azirine 4. On the other hand, the products (isoxazole 2 and oxazole 3) generated from the ketone form and from the enolate form are the same, but the reaction mechanisms are apparently different. The results demonstrate ambident-like reactivity of neutral ketone in the 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanone system.

20.
J Org Chem ; 83(21): 13063-13079, 2018 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-30284439

RESUMEN

ß-Strands are formed by extended linear peptide chains that are usually paired to form ß-sheet structure through interstrand hydrogen bonding. Linking a structured organic molecule with α-amino acid(s) can enforce or stabilize ß-strand-like extended structures of the jointed amino acids. Spectroscopic and simulation studies indicated that the presence of a C-terminal 7-azabicyclo[2.2.1]heptane amine (Abh) favors a ß-strand-like extended conformation of the adjacent α-amino acid on the N side. The bridgehead substitution of the Abh unit biases the amide cis-trans equilibrium of the adjacent α-amino acid residue to cis conformation. The proximity, specified by the presence of bond paths (such as H-H bond path) between the bridgehead proton of Abh and the α-proton of the α-amino acid provides a driving force favoring the extended conformation, which is independent of solvents. These results provide a basis for de novo design of ß-strand-mimicking extended peptides by using ß-strand enforcer/stabilizer even in the absence of the interstrand hydrogen bonding.


Asunto(s)
Aminoácidos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Simulación de Dinámica Molecular , Conformación Proteica en Lámina beta , Espectrometría Raman
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