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1.
Bioorg Med Chem Lett ; 29(18): 2681-2685, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383588

RESUMO

Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Fenotiazinas/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Esfingolipídeos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Estrutura Molecular , Oxazinas/química , Fenotiazinas/química , Proteína Fosfatase 2/metabolismo , Esfingolipídeos/química , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 159: 217-242, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30292898

RESUMO

A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Esfingosina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Camundongos , Estrutura Molecular , Esfingosina/síntese química , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-Atividade
3.
Org Biomol Chem ; 16(18): 3402-3414, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29675532

RESUMO

A stereodivergent strategy was devised to obtain enantiopure cis and trans 5-aminopipecolic acids (5-APAs) in suitably protected forms to be employed in peptide synthesis as conformationally constrained α- and δ-amino acids. The cis isomer was used as a δ-amino acid to construct a cyclic RGD-containing peptidomimetic, the ability of which to compete with biotinylated vitronectin for binding with the isolated αVß3 integrin was measured (IC50 = 4.2 ± 0.9 nM). A complete 1H NMR and computational conformational analysis was performed to elucidate the reasons for the high affinity of this cyclic peptidomimetic in comparison with cilengitide.


Assuntos
Integrina alfaVbeta3/metabolismo , Peptídeos Cíclicos/síntese química , Peptidomiméticos/síntese química , Ácidos Pipecólicos/síntese química , Aminação , Técnicas de Química Sintética/métodos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Ácidos Pipecólicos/química , Ácidos Pipecólicos/farmacologia , Ligação Proteica , Estereoisomerismo
4.
Org Biomol Chem ; 15(32): 6826-6836, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28782780

RESUMO

The conformational analysis of linear and cyclic peptides incorporating 2,3-methanopipecolic acids (or Cyclopropane Pipecolic Acids, CPAs) as conformationally constrained α-amino acids is reported. Compared to peptides containing proline or pipecolic acid, a striking increase of the cis isomer (42-92%) around the CPA amide bond is observed, both in water and organic solvents, when these unnatural amino acids are embodied in linear amino acid sequences. The rotational barrier around the same bond in water was calculated, giving results comparable to that for the prolyl cis/trans isomerization. In organic solvents, CPAs at the i + 2 position of a peptide induce the formation of a type VIa ß-turn secondary structure. When incorporated into a cyclic peptide, the cis geometry around the 2,3-methanopipecolic amide bond still prevails and, in the example studied herein (a cyclic RGD-containing ligand of αVß3 integrin mimicking Cilengitide), conservation of the backbone geometry and side chain spatial orientation of the native peptide is also found. Given the importance of the proline cis/trans isomerism in many biological processes, CPAs could be useful as proline mimetics for probing protein-ligand interactions and generating novel bioactive compounds.


Assuntos
Peptídeos/química , Peptídeos/síntese química , Ácidos Pipecólicos/química , Conformação Molecular , Ácidos Pipecólicos/síntese química
5.
Bioorg Med Chem ; 24(4): 703-11, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26753814

RESUMO

4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50=2.4nM) toward the αvß3 integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the α5ß1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual αvß3 and α5ß1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy.


Assuntos
Ciclopropanos/farmacologia , Integrina alfaVbeta3/metabolismo , Peptídeos Cíclicos/química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Ácidos Pipecólicos/farmacologia , Receptores de Vitronectina/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclopropanos/química , Relação Dose-Resposta a Droga , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Células K562 , Ligantes , Modelos Moleculares , Estrutura Molecular , Peptidomiméticos/síntese química , Ácidos Pipecólicos/química , Receptores de Vitronectina/antagonistas & inibidores , Relação Estrutura-Atividade
6.
Chemistry ; 20(35): 11187-203, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-25069617

RESUMO

The synthesis and evaluation of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for linear and cyclic peptidomimetics is reported. A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids were prepared by means of the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived enol phosphates, followed by OH-directed cyclopropanation. CPAs were successfully introduced into a linear peptide sequence to assess the cis/trans isomerism about the pipecolic acid peptide bond, and in a cyclic peptidomimetic that bore the Arg-Gly-Asp (RGD) sequence, which displayed nanomolar activity as antagonist of the αvß3 integrin in M21 human melanoma cells. Thus, CPAs appear to be suitable for the generation of novel peptidomimetics for drug discovery.


Assuntos
Ciclopropanos/química , Integrina alfaVbeta3/química , Oligopeptídeos/química , Peptídeos/síntese química , Peptidomiméticos , Ácidos Pipecólicos/síntese química , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Oligopeptídeos/metabolismo , Peptídeos/química , Ácidos Pipecólicos/química , Ligação Proteica
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