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1.
Amino Acids ; 54(2): 299-310, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35037098

RESUMEN

An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH4. In the last step, the cleavage of N-Cbz group under hydrogenolysis followed by the hydrolysis of the phosphonate or phosphinate functionalities, led to the target cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic acids, respectively.


Asunto(s)
Organofosfonatos , Ácidos Pipecólicos , Hidrólisis
2.
J Nat Prod ; 85(4): 787-803, 2022 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-35175765

RESUMEN

In this study, a series of novel 3-seco-A derivatives of the natural triterpenes α-amyrin (1) and 3-epilupeol (2) were synthesized by a one-pot radical scission-oxidation procedure and evaluated in vitro and in vivo for their capacity to inhibit the inflammatory process. For the in vitro studies, the trans-4-hydroxy-l-proline methyl ester derivatives (1f and 2f) were consistently effective in inhibiting NO, IL-6, and TNF-α secretion, as well as inhibition of NF-κB activation, in RAW cells stimulated by LPS. The further in vivo anti-inflammatory study revealed that the trans-4-hydroxy-l-proline methyl ester derivatives (1f and 2f), together with 1g, were the most effective in inhibiting TPA-induced edema. Interestingly, the α-amyrin derivatives were the most potent inhibitors of COX-2, but inhibited COX-1 only to some extent. The hydroxyl derivative (1c) was selective for COX-2 inhibition (66.3 ± 1.1% at 17.5 µM) without affecting the COX-1 isoform and did not present toxicity. Molecular docking studies revealed that these compounds bind with their polar region in the cavity over Arg-120, and their lipophilic part is orientated to the HEM cofactor similarly to the natural substrate arachidonic acid in the catalytic site of COX-2. These results indicated that seco-A ursane derivatives could be considered promising candidates for the future development of selective NF-κB and COX-2 inhibitors.


Asunto(s)
FN-kappa B , Ácido Oleanólico , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Ésteres , Hidroxiprolina , Lipopolisacáridos/farmacología , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Ácido Oleanólico/farmacología , Triterpenos Pentacíclicos
3.
Bioorg Med Chem ; 27(12): 2376-2386, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-30635220

RESUMEN

In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9-34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.


Asunto(s)
Antiinflamatorios/uso terapéutico , Etanolaminas/uso terapéutico , Inflamación/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Relación Estructura-Actividad Cuantitativa , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Etanolaminas/síntesis química , Etanolaminas/química , Ratones , Estructura Molecular , Monocitos/metabolismo , Neutrófilos/metabolismo , Organofosfonatos/síntesis química , Organofosfonatos/química
4.
Molecules ; 24(2)2019 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-30650579

RESUMEN

A straightforward and novel method for transformation of readily available 1,3-benzoxazines to secondary phosphonates and α-aminophosphonates using boron trifluoride etherate as catalyst is developed. The formation of phosphonates proceeds through ortho-quinone methide (o-QM) generated in situ, followed by a phospha-Michael addition reaction. On the other hand, the α-aminophosphonates were obtained by iminium ion formation and the subsequence nucleophilic substitution of alkylphosphites. This method can be also used for the preparation of o-hydroxybenzyl ethers through oxa-Michael addition.


Asunto(s)
Benzoxazinas/química , Organofosfonatos/síntesis química , Catálisis , Espectroscopía de Resonancia Magnética , Estructura Molecular , Organofosfonatos/química
5.
Biopolymers ; 104(5): 650-62, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25808670

RESUMEN

The creation of peptide libraries by site-selective modification of a few peptide substrates would increase the efficiency of discovery processes, but still is a real synthetic challenge. The site-selective modification of small peptides at serine or threonine residues, by using a short scission-addition procedure, allows the preparation of peptides with unnatural α-aryl glycines. In a similar way, the scission of hydroxyproline residues is the key step in the production of optically pure α-alkyl glycines which are precursors or components of branched peptides. With these versatile processes, a single peptide can be transformed into a variety of peptide derivatives. The process takes place under mild conditions, and good global yields are obtained. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 650-662, 2015.


Asunto(s)
Glicina/química , Péptidos/química , Péptidos/síntesis química , Serina/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Especificidad por Sustrato , Treonina/química
6.
J Org Chem ; 80(19): 9379-91, 2015 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-26151417

RESUMEN

The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes but still is a difficult synthetic challenge. Herein, we introduce natural hydroxyproline as a convertible unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, homoserine lactones, and Agl lactams, and to achieve the mild, efficient, and site-selective modification of peptides. A domino process is used to cleave the customizable Hyp unit under mild, metal-free conditions. Both terminal and internal positions can be modified, and similar customizable units can be differentiated. The resulting products possess two reactive chains which can be manipulated independently. The versatility and scope of this process is highlighted by its application to the ligation of two peptide chains, and the generation of peptides with several chains and peptides with conformational restrictions.


Asunto(s)
Hidroxiprolina/química , Péptidos/química , Fenómenos Bioquímicos , Ligadura , Conformación Molecular
7.
Org Biomol Chem ; 12(47): 9547-56, 2014 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-25333212

RESUMEN

The metal-free, direct conversion of readily available proline derivatives into 2-aryl-3-iodopyrrolidines is carried out under mild conditions and in good yields, using a sequential radical decarboxylation-oxidation-iodination-arylation reaction. These iodinated pyrrolidines are valuable precursors of other compounds. For instance, they can be cyclized to tricyclic compounds or undergo dehalogenation to 2-aryl-2,5-dihydro-1H-pyrroles, which are iminosugar and 2-arylpyrrole precursors. This process provides a short pathway to a variety of alkaloid and drug analogues of potential pharmaceutical interest.


Asunto(s)
Prolina/química , Pirrolidinas/síntesis química , Catálisis , Descarboxilación , Halogenación , Oxidación-Reducción , Pirroles/síntesis química , Pirroles/química , Pirrolidinas/química , Estereoisomerismo
8.
Org Lett ; 15(22): 5778-81, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24171384

RESUMEN

The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes, but still is a difficult synthetic challenge. Herein natural hydroxyproline is introduced as a "convertible" unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, and to achieve the mild, efficient, and site-selective modification of peptides.


Asunto(s)
Aminoácidos/química , Hidroxiprolina/química , Péptidos/química , Secuencia de Aminoácidos , Estructura Molecular , Estereoisomerismo
9.
Org Lett ; 13(13): 3426-9, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21615165

RESUMEN

Common ß-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-pot decarboxylation-alkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl groups, generally in high yields. A variation of the process (decarboxylation-Diels-Alder) allows the formation of bi- and polycyclic systems, which are useful precursors of alkaloid cores or iminosugars.


Asunto(s)
Amino Alcoholes/síntesis química , Alquilación , Estructura Molecular , Estereoisomerismo
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