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1.
PLoS One ; 12(8): e0182147, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28763484

RESUMO

We performed an analysis of possible mechanisms of ligand recognition in the human nose. The analysis is based on in vivo odor threshold determination and in vitro Ca2+ imaging assays with a C/Si/Ge/Sn switch strategy applied to the compounds Lilial and Bourgeonal, to differentiate between different molecular mechanisms of odorant detection. Our results suggest that odorant detection under threshold conditions is mainly based on the molecular shape, i.e. the van der Waals surface, and electrostatics of the odorants. Furthermore, we show that a single olfactory receptor type is responsible for odor detection of Bourgeonal at the threshold level in humans in vivo. Carrying out a QM analysis of vibrational energies contained in the odorants, there is no evidence for a vibration-based recognition.


Assuntos
Nariz/fisiologia , Odorantes , Neurônios Receptores Olfatórios/fisiologia , Olfato , Cálcio/química , Simulação por Computador , Humanos , Ligantes , Relação Quantitativa Estrutura-Atividade , Receptores Odorantes/fisiologia , Análise de Regressão , Limiar Sensorial , Propriedades de Superfície , Temperatura
2.
Chem Biodivers ; 11(11): 1675-87, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25408317

RESUMO

5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties.


Assuntos
Aldeídos/química , Convallaria/química , Odorantes , Compostos de Organossilício/síntese química , Silício/química , Estrutura Molecular , Compostos de Organossilício/química
3.
Chemistry ; 19(34): 11396-408, 2013 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-23843352

RESUMO

A series of silicon-containing derivatives of the polycyclic musk odorant galaxolide (4 a) was synthesized, that is, disila-galaxolide ((4RS,7SR)-4 b/(4RS,7RS)-4 b), its methylene derivative rac-9, and its nor analogue rac-10. The tricyclic title compounds with their 7,8-dihydro-6,8-disila-6 H-cyclopenta[g]isochromane skeleton were prepared in multistep syntheses by using a cobalt-catalyzed [2+2+2] cycloaddition of the mono- yne H2C=CHCH2 OCH2 C≡CB(pin) (B(pin)=4,4,5,5-tetramethyl-1,3,2-di- oxaborolan-2-yl) with the diynes H2C=C[Si(CH3 )2 C≡CH]2 or H2C- [Si(CH3)2 C≡CH]2 as the key step. Employing [Cr(CO)3 (MeCN)3 ] as an auxiliary, the disila-galaxolide diastereomers (4RS,7SR)-4 b and (4RS,7RS)-4 b could be chromatographically separated through their tricarbonylchromium(0) complexes, followed by oxidative decomplexation. The identity of the title compounds and their precursors was established by elemental analyses and multinuclear NMR spectroscopic studies and in some cases additionally by crystal structure analyses. Compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10 were characterized for their olfactory properties, including GC-olfactory studies of the racemic compounds on a chiral stationary phase. As for the parent galaxolide stereoisomers 4 a, only one enantiomer of the silicon compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10, smelt upon enantioselective GC-olfactometry, which according to the elution sequence is assumed to be also (4S)-configured as in the case of the galaxolide stereoisomers. The disila-analogues (4S,7R)-4 b and (4S,7S)-4 b were, however, about one order of magnitude less intense in terms of their odor threshold than their parent carbon compounds (4S,7R)-4 a and (4S,7S)-4 a. The introduction of a 7-methylene group in disila-galaxolide (4 b→rac-9) improved the odor threshold by a factor of two. With the novel silicon-containing galaxolide derivatives, the presumed hydrophobic bulk binding pocket of the corresponding musk receptor(s) could be characterized in more detail, which could be useful for the design of novel musk odorants with an improved environmental profile.

4.
Org Biomol Chem ; 10(34): 6914-29, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22814352

RESUMO

Silicon chemistry offers the potential to tune the effects of biologically active organic molecules. Subtle changes in the molecular backbone caused by the exchange of a carbon atom for a silicon atom (sila-substitution) can significantly alter the biological properties. In this study, the biological effects of a two-fold sila-substitution in the synthetic retinoids EC23 (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid (4a)) and TTNN (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-naphthoic acid (7a)) as well as their corresponding analogues with an indane instead of a 1,2,3,4-tetrahydronaphthalene skeleton (compounds 5a and 8a) were investigated. Two-fold C/Si exchange in 4a, 5a, 7a and 8a leads to the silicon-analogues disila-EC23 (4b), 5b, disila-TTNN (7b) and 8b, which contain a 1,2,3,4-tetrahydro-1,4-disilanaphthalene (4b, 7b) or 1,3-disilaindane skeleton (5b, 8b). Exchange of the SiCH(2)Si moiety of 5b for an SiOSi fragment leads to the disiloxane 6 (2-oxa-1,3-disilaindane skeleton). The EC23 derivative 5a, the TTNN derivative 8a and the silicon-containing analogues 4b, 5b, 6, 7b and 8b were synthesised, and the biological properties of the C/Si pairs 4a/4b, 5a/5b, 7a/7b and 8a/8b and compound 6 were evaluated in vivo using RAR isotype-selective reporter cells. EC23 (4a) and its derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR agonists, which are even more potent than the powerful reference compound TTNPB. Disila-substitution of EC23 (4a) and 5a leads to a moderate decrease in RARα activation, whereas the RARß,γ activation is almost not affected. In contrast, two-fold C/Si exchange in the weak retinoid agonist TTNN (7a) and 8a resulted in considerably different effects: a significant increase (7a→7b) and almost no change (8a→8b) in transcription activation potential for all three RAR isotypes. Disila-TTNN (7b) can be regarded as a powerful RARß,γ-selective retinoid.


Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Compostos de Organossilício/síntese química , Compostos de Organossilício/farmacologia , Retinoides/síntese química , Retinoides/farmacologia , Silício/química , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Benzoatos/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética , Células HeLa , Humanos , Modelos Moleculares , Conformação Molecular , Naftalenos/química , Compostos de Organossilício/química , Retinoides/química , Tetra-Hidronaftalenos/química , Ativação Transcricional/efeitos dos fármacos
5.
ChemMedChem ; 7(3): 523-32, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22076883

RESUMO

The 1'-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4'-piperidine] derivatives 1 a-4 a [for which organyl=benzyl (1 a), 4-methoxybenzyl (2 a), 2-phenylethyl (3 a), or 3-methylbut-2-enyl (4 a)] are high-affinity, selective σ1 ligands. The corresponding sila-analogues 1 b-4 b (replacement of the carbon spirocenter with a silicon atom) were synthesized in multistep syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1 b⋅HCl-4 b⋅HCl. Compounds 1 a⋅HCl-4 a⋅HCl and 1 b⋅HCl-4 b⋅HCl were structurally characterized by NMR spectroscopy (¹H, ¹³C, ²9Si) in solution, and the C/Si analogues 3 a⋅HCl and 3 b⋅HCl were studied by single-crystal X-ray diffraction. These structural investigations were complemented by computational studies. The σ1 and σ2 receptor affinities of the C/Si pairs 1 a/1 b-4 a/4 b were studied with radioligand binding assays. The σ1 receptor affinity of the silicon compounds 1 b-4 b is slightly higher than that of the corresponding carbon analogues 1 a-4 a. Because affinity for the σ2 receptor is decreased by the C/Si exchange, the σ1/σ2 selectivity of the silicon compounds is considerably improved, indicating that the C→Si switch strategy is a powerful tool for modulating both pharmacological potency and selectivity.


Assuntos
Carbono/química , Naftalenos/síntese química , Fármacos Neuroprotetores/síntese química , Piperidinas/síntese química , Receptores sigma/agonistas , Silício/química , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cristalografia por Raios X , Cobaias , Humanos , Ligantes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Naftalenos/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Receptores sigma/metabolismo , Relação Estrutura-Atividade
6.
ChemMedChem ; 6(8): 1509-17, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21726055

RESUMO

Twofold sila-substitution (C/Si exchange) of the clinically used RXR-selective retinoid agonist bexarotene leads to disila-bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa-cell-based RXR assay. Formal exchange of the SiCH2CH2 Si group in disila-bexarotene with a SiCH2Si or SiOSi moiety leads to the disila-bexarotene analogues 8 and 9. The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HC≡C(CH3)2SiCH2Si(CH3)2C≡CH and HC≡C(CH3)2SiOSi(CH3)2C≡CH, respectively. The key step in the syntheses of 8 and 9 is a cobalt-catalyzed [2+2+2] cycloaddition reaction that affords the 1,3-disilaindane and 2-oxa-1,3-disilaindane skeletons. Disila-bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all-trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon-containing bexarotene analogues disila-bexarotene, 8, and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon-containing analogues disila-bexarotene, 8, and 9, may partially act to induce cell differentiation.


Assuntos
Receptores X de Retinoides/agonistas , Silício/química , Células-Tronco/efeitos dos fármacos , Tetra-Hidronaftalenos/química , Bexaroteno , Diferenciação Celular , Proliferação de Células , Cristalografia por Raios X , Humanos , Conformação Molecular , Receptores X de Retinoides/metabolismo , Células-Tronco/citologia , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia
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