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1.
Chemistry ; 30(19): e202304126, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38221894

RESUMEN

Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non-polymeric glycosidase inhibitor have been obtained with cyclopeptoid-based inhibitors of Jack bean α-mannosidase (JBα-man). Here, we report a structure-activity relationship (SAR) study based on the top-down deconstruction of best-in-class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate-binding, resulting from the formation of a cross-linked complex between a multivalent inhibitor and two dimeric JBα-man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors.


Asunto(s)
Glicósido Hidrolasas , Iminoazúcares , Humanos , Glicósido Hidrolasas/metabolismo , Iminoazúcares/química , alfa-Manosidasa , Relación Estructura-Actividad
2.
Chemistry ; 30(36): e202400904, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38699895

RESUMEN

Two new chiral 1,2,3-triazole-containing macrocyclic oligoamides (i. e.: triazolopeptoid 4 and 5) were obtained through solid-phase synthesis of linear precursors followed by high dilution macrocyclization reaction. Theoretical (DFT) and spectroscopic (NMR) studies revealed the intricate interplay between the Nα-chiral side chains and their conformational attitudes. BH3-mediated reduction of the tertiary amide groups of known 1-3 and newly synthesized 4 gave novel azamacrocycles 6-9. Detection of borane complexes of azamacrocycles 6 and 9 (i. e.: 10 and 11), corroborated by X-ray diffraction studies, demonstrated the peculiar properties of 1,2,3-triazole-containing macrorings.

3.
J Org Chem ; 89(10): 7255-7262, 2024 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-38718382

RESUMEN

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.


Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Compuestos de Espiro , Estereoisomerismo , Enfermedad de Alzheimer/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Alcaloides/química , Alcaloides/síntesis química , Alcaloides/farmacología , Estructura Molecular , Benzofuranos/química , Benzofuranos/síntesis química , Benzofuranos/farmacología
4.
J Pept Sci ; 30(3): e3544, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37726947

RESUMEN

Magnetic resonance imaging (MRI) is a common medical imaging technique that provides three-dimensional body images. MRI contrast agents improve image contrast by raising the rate of water proton relaxation in specific tissues. Peptides and peptidomimetics act as scaffolds for MRI imaging agents because of their increased size and offer the possibility to engine a higher hydration value within the design. The design of a new Gd-based contrast agent must take into account high stability constants to avoid free Gd(III), with the subsequent nephrotoxicity, and high relaxivity values. This review analyzes various synthetic approaches, reports studies of relaxometric parameters, and focuses on the description and application of Gd(III)-chelates based on peptide and peptidomimetic scaffolds. In addition, the X-ray molecular structures of three DOTA complexes will be reported to emphasize the necessity of using the X-ray diffraction analysis to identify the coordination sphere of the metals and the mechanism of action of the compounds.


Asunto(s)
Medios de Contraste , Peptidomiméticos , Medios de Contraste/química , Gadolinio/química , Imagen por Resonancia Magnética/métodos , Péptidos
5.
Org Biomol Chem ; 19(34): 7420-7431, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34397051

RESUMEN

A variety of cyclen and hexacyclen derivatives decorated with (S)-1-phenylethyl side chains or (S)-pyrrolidine units have been prepared via a reductive approach from the corresponding cyclic peptoids containing N-(S)-(1-phenylethyl)glycine and l-proline residues. Spectroscopic and DFT studies on their Na+ complexes show that point chirality and ring size play a crucial role in controlling the structural dynamism of 1,2-diaminoethylene units and pendant arms. The detection of highly symmetric C4- and C3-symmetric metalated species demonstrates that a full understanding of the relationship between the structure and conformational properties of peraza-macrocyclic metal complexes is possible.


Asunto(s)
Peptoides
6.
J Org Chem ; 85(11): 7476-7484, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32403930

RESUMEN

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

7.
Chemistry ; 25(29): 7131-7141, 2019 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-30779872

RESUMEN

The first highly enantioselective arylogous Michael reaction (AMR) of 3-unsubstituted phthalides has been described. This phase-transfer methodology, which uses catalytic amounts of KOH/18-crown-6 catalyst in mesitylene in the presence of N,O-bis(trimethylsilyl)acetamide (BSA), gives access to a broad range of 3-monosubstituted phthalides with high levels of syn diastereoselectivity and good yields, starting from 3-unsubstituted derivatives and diverse α,ß-unsaturated carbonyl compounds. The reaction also applies to unactivated 3-alkyl phthalides to afford 3,3-dialkyl derivatives. A plausible mechanism has been suggested. DFT analysis of possible transition states gives a rationale of the high syn diastereoselectivity observed and its correlation with the solvent's dielectric constant.

8.
J Org Chem ; 83(20): 12648-12663, 2018 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-30226388

RESUMEN

Peptoids are oligomers of N-substituted glycines with predictable folding and strong potentials as guest-binding receptor molecules. In this contribution, we investigate the structural features of a series of designed symmetric cyclic octamer peptoids (with methoxyethyl/propargyl side chains) as free hosts and reveal their morphologic changes in the presence of sodium and alkylammonium guests as tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts, reporting the first case of reversible adaptive switching between defined conformational states induced by cationic guests (Na+ and benzylammonium ion) in the peptoid field. The reported results are based on 1H NMR data, theoretical models, and single-crystal X-ray diffraction analysis. They represent initial steps toward deciphering the unique conformational states of cyclic octamer peptoids as supramolecular hosts with the aim to fully disclose their functional and dynamic properties.


Asunto(s)
Péptidos Cíclicos/síntesis química , Peptoides/síntesis química , Compuestos de Amonio/química , Boratos/química , Cationes/química , Modelos Moleculares , Conformación Proteica , Sodio/química , Técnicas de Síntesis en Fase Sólida , Estereoisomerismo , Termodinámica
9.
J Org Chem ; 82(13): 6629-6637, 2017 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-28561585

RESUMEN

The fluoride-promoted vinylogous Mukaiyama-Michael reaction of 2-[(trimethylsilyl)oxy]furan with diverse α,ß-unsaturated ketones is described. The TBAF-catalyzed VMMR afforded high anti-diastereoselectivity irrespective of the solvents used. The KF/crown ethers catalytic systems proved to be highly efficient in terms of yields and resulted in a highly diastereoselective unprecedented solvent/catalyst switchable reaction. Anti-adducts were obtained as single diastereomers or with excellent diastereoselectivities when benzo-15-crown-5 in CH2Cl2 was employed. On the other hand, high syn-diastereoselectivities (from 73:27 to 96:4) were achieved by employing dicyclohexane-18-crown-6 in toluene. On the basis of DFT calculations, the catalysts/solvent-dependent switchable diastereoselectivities are proposed to be the result of loose or tight cation-dienolate ion pairs.

10.
Mar Drugs ; 15(3)2017 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-28335479

RESUMEN

A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1-19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility.


Asunto(s)
Péptidos Cíclicos/química , Organismos Acuáticos/química , Humanos , Prolina/química , Reproducibilidad de los Resultados
11.
J Org Chem ; 81(6): 2494-505, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26914694

RESUMEN

The effects of substituents and cavity size on catalytic efficiency of proline-rich cyclopeptoids under phase-transfer conditions were studied. High affinity constants (Ka) for the sodium and potassium cations, comparable to those reported for crown ethers, were observed for an alternated N-benzylglycine/L-proline hexameric cyclopeptoid. This compound was found to catalyze the alkylation of N-(diphenylmethylene)glycine cumyl ester in values of enantioselectivities comparable with those reported for the Cinchona alkaloid ammonium salts derivatives (83-96% ee), and with lower catalyst loading (1-2.5% mol), in the presence of a broad range of benzyl, allyl and alkyl halides.


Asunto(s)
Arginina/química , Derivados del Benceno/química , Alcaloides de Cinchona/química , Glicina/análogos & derivados , Péptidos Cíclicos/química , Prolina/química , Alquilación , Glicina/química , Estructura Molecular , Prolina/análogos & derivados , Estereoisomerismo
12.
Chem Commun (Camb) ; 58(34): 5253-5256, 2022 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-35388839

RESUMEN

Enantiomorphic right- and left-handed polyproline type I helices in four cyclic dodecapeptoids with methoxyethyl and propargyl side chains are observed for the first time by single crystal X-ray diffraction. The peculiar absence of NH⋯OC hydrogen bonds in peptoids unveils the role of intramolecular backbone-to-backbone CO⋯CO interactions and CH⋯OC hydrogen bonds in the stabilization of the macrocycle conformation. Moreover, intramolecular backbone-side chain C5 CH⋯OC hydrogen bonds emerge as a stabilizing factor.


Asunto(s)
Peptoides , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Peptoides/química , Estructura Secundaria de Proteína
13.
Org Lett ; 24(42): 7752-7756, 2022 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-36223077

RESUMEN

Head-to-tail cyclization of linear oligoamides containing 4-benzylaminomethyl-1H-1,2,3-triazol-1-yl acetic acid monomers afforded a novel class of "extended macrocyclic peptoids". The identification of the conformation in solution for a cyclodimer and the X-ray crystal structure of a cyclic tetraamide are reported.


Asunto(s)
Peptoides , Peptoides/química , Modelos Moleculares , Conformación Molecular , Ciclización
14.
Org Lett ; 21(18): 7365-7369, 2019 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-31469569

RESUMEN

Peraza-macrocycles form chelates of high thermodynamic and kinetic stability useful in diagnostic imaging (MRI, SPECT, PET), in coordination chemistry, and as catalysts. In this letter, we report an advantageous method to prepare these compounds via BH3-induced reduction of cyclic peptoids. Using this procedure, 10 homo- and heterosubstituted aza-coronands, with different sizes and side chains, have been synthesized from the corresponding cyclic oligoamides. Solid structures of free, protonated, and Na+ coordinated polyaza-derivatives have been disclosed by single-crystal X-ray diffraction analysis.


Asunto(s)
Compuestos Macrocíclicos/síntesis química , Peptoides/química , Cristalografía por Rayos X , Cinética , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Termodinámica
15.
Org Lett ; 19(16): 4383-4386, 2017 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-28792223

RESUMEN

The first arylogous Michael reaction of 3-aryl phthalides has been developed. The reaction, promoted by catalytic amounts of KOH or K3PO4 and dibenzo-18-crown-6, affords the corresponding 3,3-disubstituted phthalides in good to high yields and as single diastereomers in nearly all studied cases.

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