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1.
Chemistry ; 26(16): 3504-3508, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31944467

RESUMO

A highly enantioselective, organocatalytic, and scalable synthesis of a very unusual cis-decalin-cis-hydrindane tricyclic diterpenoid system has been achieved. Despite the prevalent pharmacological space that the related trans,trans and trans,cis-systems occupy, there have been no reports of an asymmetric synthesis of the cis,cis systems in the literature until now. We demonstrate the flexibility of our approach not only through access to a diverse range of products, all of which are attained in exceptionally high selectivities, but also by showing their easy conversion to the corresponding trans,cis-system and other derivatives.

2.
J Am Chem Soc ; 142(3): 1382-1393, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31820966

RESUMO

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the cis-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding trans-system can be fulfilled by several competing helical structures.

3.
Adv Mater ; 31(43): e1902407, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512304

RESUMO

Molecular vibrations play a critical role in the charge transport properties of weakly van der Waals bonded organic semiconductors. To understand which specific phonon modes contribute most strongly to the electron-phonon coupling and ensuing thermal energetic disorder in some of the most widely studied high-mobility molecular semiconductors, state-of-the-art quantum mechanical simulations of the vibrational modes and the ensuing electron-phonon coupling constants are combined with experimental measurements of the low-frequency vibrations using inelastic neutron scattering and terahertz time-domain spectroscopy. In this way, the long-axis sliding motion is identified as a "killer" phonon mode, which in some molecules contributes more than 80% to the total thermal disorder. Based on this insight, a way to rationalize mobility trends between different materials and derive important molecular design guidelines for new high-mobility molecular semiconductors is suggested.

4.
Acta Crystallogr C Struct Chem ; 75(Pt 7): 904-909, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271378

RESUMO

A new crystalline form of αß-D-lactose (C12H22O11) has been prepared by the rapid drying of an approximately 40% w/v syrup of D-lactose. Initially identified from its novel powder X-ray diffraction pattern, the monoclinic crystal structure was solved from a microcrystal recovered from the generally polycrystalline mixed-phase residue obtained at the end of the drying step. This is the second crystalline form of αß-D-lactose to be identified and it has a high degree of structural three-dimensional similarity to the previously identified triclinic form.

5.
Eur J Pharm Sci ; 123: 268-276, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30048801

RESUMO

Conjugation of small molecule agonists of Toll-like receptor 7 (TLR7) to proteins, lipids, or polymers is known to modulate potency, and the physical form or formulation of these conjugates is likely to have a major effect on their immunostimulatory activity. Here, we studied the effect of formulation on potency of a 1,2­di­(9Z­octadecenoyl)­sn­glycero­3­phosphoethanolamine (DOPE) conjugated TLR7 agonist (DOPE-TLR7a) alongside assessing physical form using Dynamic Light Scattering (DLS), Nanosight Particle Tracking (NTA) analysis and Small Angle X-ray Scattering (SAXS). A very high potency of DOPE-TLR7a conjugate (EC50 around 9 nM) was observed either when prepared by direct dilution from DMSO or when formulated into 400-700 nm large multilamella liposomes containing dimethyldioctadecylammonium bromide salt (DDA) and DOPE. When prepared by dissolution in DMSO followed by dilution in aqueous culture medium, 93 ±â€¯5 nm nanoparticles were formed. Without dilution from solution in DMSO, no nanoparticles were observed and no immunostimulatory activity could be detected without this formulation step. SAXS analysis of the conjugate after DMSO dissolution/water dilution revealed a lamellar order with a layer spacing of 68.7 Å, which correlates with arrangement in groups of 3 bilayers. The addition of another immunostimulatory glycolipid, trehalose­6,6­dibehenate (TDB), to DOPE:DDA liposomes gave no further increase in immunostimulatory activity beyond that provided by incorporating DOPE-TLR7a. Given the importance of nanoparticle or liposomal formulation for activity, we conclude that the major mechanism for increased potency when TLR7 agonists are conjugated to macromolecules is through alteration of physical form.


Assuntos
Adjuvantes Imunológicos/farmacologia , Benzaldeídos/farmacologia , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/agonistas , Nanopartículas , Fosfatidiletanolaminas/química , Purinas/farmacologia , Receptor 7 Toll-Like/agonistas , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/metabolismo , Animais , Benzaldeídos/química , Benzaldeídos/metabolismo , Relação Dose-Resposta a Droga , Composição de Medicamentos , Lipossomos , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Purinas/química , Purinas/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
6.
J Pharm Sci ; 107(8): 2042-2047, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29679705

RESUMO

Crystal structure determination from powder diffraction data (SDPD) using the DASH software package is evaluated for data recorded using transmission capillary, transmission flat plate, and reflection flat plate geometries on a selection of pharmaceutical compounds. We show that transmission capillary geometry remains the best option when crystal structure determination is the primary consideration and, as expected, reflection flat plate geometry is not recommended for SDPD because of preferred orientation effects. However, the quality of crystal structures obtained from transmission plate instruments can be excellent, and the convenience factor for sample preparation, throughput, and retrieval is higher than that of transmission capillary instruments. Indeed, it is possible to solve crystal structures within an hour of a polycrystalline sample arriving in the laboratory, which has clear implications for making small-molecule crystal structures more routinely available to the practicing laboratory medicinal chemist. With appropriate modifications to crystal structure determination software, it can be imagined that SDPD could become a rapid turn-around walk-up analytical service in high-throughput chemical environments.


Assuntos
Cristalografia por Raios X/métodos , Preparações Farmacêuticas/química , Antagonistas Adrenérgicos beta/química , Antibacterianos/química , Carvedilol/química , Cefadroxila/química , Modelos Moleculares , Difração de Pó/métodos , Software , Difração de Raios X/métodos
7.
Mol Pharm ; 15(4): 1476-1487, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29490140

RESUMO

By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and molecular modeling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influence the relative orientation of a methyl group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the p Ka of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.


Assuntos
Isoquinolinas/química , Sulfonamidas/química , Cristalização/métodos , Cristalografia por Raios X/métodos , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Conformação Molecular , Pós/química , Sais/química , Difração de Raios X/métodos
8.
J Agric Food Chem ; 66(10): 2449-2458, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28215083

RESUMO

The popularity of smoked foodstuffs such as sauces, marinades, and rubs is on the rise. However, during the traditional smoking process, in addition to the desirable smoky aroma compounds, harmful polycyclic aromatic hydrocarbons (PAHs) are also generated. In this work, a selective filter was developed that reduces PAH concentrations in a smoke by up to 90% while maintaining a desirable smoky flavor. Preliminary studies using a cocktail of 12 PAHs stirred with a zeolite showed the potential for this zeolite to selectively remove PAHs from a simple solution. However, pretreatment of the smoke prior to application removed the PAHs more efficiently and is more widely applicable to a range of food ingredients. Although volatile analysis showed that there was a concomitant reduction in the concentration of the smoky compounds such as 2-methoxyphenol (guaiacol), 2-methylphenol ( o-cresol), and the isoeugenols, sensory profiling showed that the difference in perception of flavor was minimal.


Assuntos
Filtração/métodos , Aromatizantes/química , Hidrocarbonetos Policíclicos Aromáticos/química , Fumaça/análise , Zeolitas/química , Culinária , Filtração/instrumentação , Temperatura Alta , Humanos , Odorantes/análise
9.
Sci Rep ; 7(1): 5738, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720875

RESUMO

The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio-chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio-coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents.


Assuntos
Plaquetas/efeitos dos fármacos , Fibrinolíticos/farmacologia , Flavonoides/farmacologia , Hemostasia/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Rutênio/farmacologia , Trombose/prevenção & controle , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Fibrinolíticos/administração & dosagem , Fibrinolíticos/síntese química , Fibrinolíticos/farmacocinética , Flavonoides/administração & dosagem , Flavonoides/farmacocinética , Humanos , Camundongos , Rutênio/administração & dosagem , Rutênio/farmacocinética
10.
Chem Commun (Camb) ; 51(70): 13558-61, 2015 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-26223465

RESUMO

An organocatalytic asymmetric synthesis of a novel, highly functionalised cyclopropane system furnished with versatile substituents and containing a quaternary centre is described. The process utilises a new bifunctional catalyst based on the cinchona alkaloid framework and the products made using this catalyst were obtained as single diastereoisomers, with very high enantioselectivities (up to 96% ee). We have also demonstrated that these resulting cyclopropanes are very useful synthetic intermediates to interesting products, such as the difficult to access δ(3)-amino acids.


Assuntos
Aminoácidos/química , Ciclopropanos/química , Quinolinas/química , Sulfonas/química , Catálise , Estrutura Molecular , Estereoisomerismo , Fatores de Tempo
11.
Chem Commun (Camb) ; 51(6): 1143-6, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25466759

RESUMO

Sensitive optical detection of nitroaromatic vapours with diketopyrrolopyrrole thin films is reported for the first time and the impact of thin film crystal structure and morphology on fluorescence quenching behaviour demonstrated.


Assuntos
Aminoácidos Aromáticos/química , Gases/análise , Nitrocompostos/química , Pirróis/química , Fluorescência , Microscopia Eletrônica de Varredura , Estrutura Molecular
12.
Chemistry ; 20(37): 11685-9, 2014 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-25082061

RESUMO

An efficient synthesis of spirocyclic triazolooxazine nucleosides is described. This was achieved by the conversion of ß-D-psicofuranose to the corresponding azido-derivative, followed by alkylation of the primary alcohol with a range of propargyl bromides, obtained by Sonogashira chemistry. The products of these reactions underwent 1,3-dipolar addition smoothly to generate the protected spirocyclic adducts. These were easily deprotected to give the corresponding ribose nucleosides. The library of compounds obtained was investigated for its antiviral activity using MHV (mouse hepatitis virus) as a model wherein derivative 3 f showed the most promising activity and tolerability.

13.
Dalton Trans ; 43(25): 9448-55, 2014 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-24821388

RESUMO

Organo-copper(i) halide complexes with a Cu4I4 cubane core and cyclic amines as ligands have been synthesized and their crystal structures have been defined. Their solid state photophysical properties have been measured and correlated with the crystal structure and packing. A unique and remarkably high luminescence quantum yield (76%) has been measured for one of the complexes having the cubane clusters arranged in a columnar structure and held together by N-HI hydrogen bonds. This high luminescence quantum yield is correlated with a slow radiationless deactivation rate of the excited state and suggests a rather strong enhancement of the cubane core rigidity bestowed by the hydrogen bond pattern. Some preliminary thin film deposition experiments show that these compounds could be considered to be good candidates for applications in electroluminescent devices because of their bright luminescence, low cost and relatively easy synthesis processes.


Assuntos
Aminas/química , Cobre/química , Iodetos/química , Luminescência , Compostos Organometálicos/química , Teoria Quântica , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular
14.
Acta Crystallogr C ; 69(Pt 11): 1251-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24192168

RESUMO

Solving pharmaceutical crystal structures from powder diffraction data is discussed in terms of the methodologies that have been applied and the complexity of the structures that have been solved. The principles underlying these methodologies are summarized and representative examples of polymorph, solvate, salt and cocrystal structure solutions are provided, together with examples of some particularly challenging structure determinations.


Assuntos
Difração de Pó , Química Farmacêutica , Cristalografia por Raios X , Modelos Moleculares , Soluções/química , Solventes/química
15.
Org Lett ; 15(6): 1386-9, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23461553

RESUMO

When ε-nitro-α,ß-unsaturated esters are added to conjugated cyanosulfones in the presence of a bifunctional thiourea catalyst, a highly stereoselective domino reaction occurs to generate complex cyclohexanes with up to four stereogenic centers, one of which is quaternary in nature. Therefore, it is demonstrated that, like nitro compounds, sulfones can undergo an asymmetric intramolecular conjugate addition to α,ß-unsaturated esters in the presence of a bifunctional organocatalyst.

17.
Acta Crystallogr C ; 68(Pt 2): m29-33, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22307244

RESUMO

Three alkaline earth metal salts of phenylacetic acid were examined and all were found to have similar structural types to analogous salts of benzoic and halobenzoic acids. Thus, a synchrotron study shows that the cations in catena-poly[[[tetraaquamagnesium(II)]-µ-phenylacetato-κ(2)O:O'] phenylacetate], {[Mg(C(8)H(7)O(2))(H(2)O)(4)](C(8)H(7)O(2))}(n), form a one-dimensional coordination polymer that propagates through Mg-O-C-O-Mg interactions involving both crystallographically independent Mg centres (Z' = 2) and through translation along the a axis. The polymeric chains pack to give alternate inorganic layers and organic bilayers. The Ca and Sr species catena-poly[[[diaqua(phenylacetato-κ(2)O,O')calcium(II)]-µ(3)-phenylacetato-1':1:1''κ(4)O:O,O':O'] monohydrate], {[Ca(C(8)H(7)O(2))(2)(H(2)O)(2)]·H(2)O}(n), and catena-poly[[[diaqua(phenylacetato-κ(2)O,O')strontium(II)]-µ(3)-phenylacetato-1':1:1''κ(4)O:O,O':O'] monohydrate], {[Sr(C(8)H(7)O(2))(2)(H(2)O)(2)]·H(2)O}(n), are essentially isostructural. Both form one-dimensional coordination polymers through a carboxylate group that forms four M-O bonds. The polymeric chains propagate via 2(1) screw axes parallel to the b axis and are further linked in the bc plane by hydrogen bonding involving the non-metal-bound water molecule. Similarly to the Mg salt, both have inorganic layers that alternate with organic bilayers.


Assuntos
Cálcio/química , Cátions/química , Magnésio/química , Metais Alcalinoterrosos/química , Compostos Organometálicos/química , Fenilacetatos/química , Sais/química , Estrôncio/química , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular
19.
Chemistry ; 15(31): 7554-68, 2009 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-19593826

RESUMO

A family of 16 isomolecular salts (3-XpyH)(2)[MX'(4)] (3-XpyH = 3-halopyridinium; M = Co, Zn; X = (F), Cl, Br, (I); X' = Cl, Br, I) each containing rigid organic cations and tetrahedral halometallate anions has been prepared and characterized by X-ray single crystal and/or powder diffraction. Their crystal structures reflect the competition and cooperation between non-covalent interactions: N-H...X'-M hydrogen bonds, C-X...X'-M halogen bonds and pi-pi stacking. The latter are essentially unchanged in strength across the series, but both halogen bonds and hydrogen bonds are modified in strength upon changing the halogens involved. Changing the organic halogen (X) from F to I strengthens the C-X...X'-M halogen bonds, whereas an analogous change of the inorganic halogen (X') weakens both halogen bonds and N-H...X'-M hydrogen bonds. By so tuning the strength of the putative halogen bonds from repulsive to weak to moderately strong attractive interactions, the hierarchy of the interactions has been modified rationally leading to systematic changes in crystal packing. Three classes of crystal structure are obtained. In type A (C-F...X'-M) halogen bonds are absent. The structure is directed by N-H...X'-M hydrogen bonds and pi-stacking interactions. In type B structures, involving small organic halogens (X) and large inorganic halogens (X'), long (weak) C-X...X'-M interactions are observed with type I halogen-halogen interaction geometries (C-X...X' approximately = X...X'-M approximately = 155 degrees), but hydrogen bonds still dominate. Thus, minor but quite significant perturbations from the type A structure arise. In type C, involving larger organic halogens (X) and smaller inorganic halogens (X'), stronger halogen bonds are formed with a type II halogen-halogen interaction geometry (C-X...X' approximately = 180 degrees; X...X'-M approximately = 110 degrees) that is electrostatically attractive. The halogen bonds play a major role alongside hydrogen bonds in directing the type C structures, which as a result are quite different from type A and B.


Assuntos
Hidrocarbonetos Halogenados/química , Modelos Moleculares , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular
20.
J Am Chem Soc ; 131(11): 3884-93, 2009 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-19253941

RESUMO

We have applied a combination of spectroscopic and diffraction methods to study the adduct formed between squaric acid and bypridine, which has been postulated to exhibit proton transfer associated with a single-crystal to single-crystal phase transition at ca. 450 K. A combination of X-ray single-crystal and very-high flux powder neutron diffraction data confirmed that a proton does transfer from the acid to the base in the high-temperature form. Powder X-ray diffraction measurements demonstrated that the transition was reversible but that a significant kinetic energy barrier must be overcome to revert to the original structure. Computational modeling is consistent with these results. Modeling also revealed that, while the proton transfer event would be strongly discouraged in the gas phase, it occurs in the solid state due to the increase in charge state of the molecular ions and their arrangement inside the lattice. The color change is attributed to a narrowing of the squaric acid to bipyridine charge-transfer energy gap. Finally, evidence for the possible existence of two further phases at high pressure is also presented.


Assuntos
Ciclobutanos/química , Piridinas/química , Pressão , Prótons , Temperatura
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