Conformational preferences of two C-glycosyl analogues of Manp-(1 → 3)-Manp, were studied using a combined method of theoretical and experimental chemistry. Molecular dynamics was utilized to provide conformational behavior along C-glycosidic bonds of methyl 3-deoxy-3-C-[(α-d-mannopyranosyl)methyl]-α-d- and l-mannopyranosides. The OPLS2005 and Glycam06 force fields were used. Simulations were performed with explicit water (TIP3P) and methanol. Results were compared with a complete conformational scan at the MM4 level with the dielectric constant corresponding to methanol. In order to verify predicted conformational preferences, vicinal 3JHH NMR coupling constants were calculated by the Karplus equation on simulated potential energy surfaces (PES). A set of new parameters for the Karplus equation was also designed. Predicted 3JHH were compared with experimental data. We also used reverse methodology, in which the 3JHH coupling constants were calculated at the DFT level for each family of (ϕ, ψ)-conformers separately and then experimental values were decomposed onto calculated 3JHH couplings in order to obtain experimentally derived populations of conformers. As an alternative method of evaluation of preferred conformers, analysis of sensitive 13C chemical shifts was introduced. We were able to thoroughly discuss several fundamental issues in predictions of preferred conformers of C-saccharides, such as the solvent effect, reliability of the force field, character of empirical Karplus equation or applicability of NMR parameters in predictions of conformational preferences in general.
Skin penetration enhancers are compounds used to facilitate the transdermal delivery of drugs that are otherwise not sufficiently permeable. Through a synthetic route implementing two series of esters, we generated transdermal penetration enhancers by a multi-step reaction with substituted 6-aminohexanoic acid. We present the synthesis of all newly prepared compounds here with structural confirmation accomplished by (1)H NMR, (13)C NMR, IR and mass spectroscopy (MS). The lipophilicity (logk) of all compounds was determined via RP-HPLC and their hydrophobicity (logP/ClogP) was also calculated using two commercially available programs. Ab initio calculations of geometry and molecular dynamic simulations were employed to investigate the 3-dimensional structures of selected compounds. The transdermal penetration-enhancing activity of all the synthesized esters were examined in vitro and demonstrated higher enhancement ratios than oleic acid. Compounds 2e (C(10) ester chain) and 2f (C(11) ester chain) exhibited the highest enhancement ratios. It can be concluded that the series non-substituted at the C((2)) position by a ω-lactam ring showed significantly higher activity than those with azepan-2-one. None of the prepared compounds penetrated through the skin. All of the investigated agents demonstrated minimal anti-proliferative activity using the SK-N-MC neuroepithelioma cell line (IC(50)>6.25μM), suggesting these analogs would have a low cytotoxic profile when administered in vivo as chemical penetration enhancers. The correlation between the chemical structure of the studied compounds and their lipophilicity is discussed in regards to transdermal penetration-enhancing activity.
- MeSH
- aplikace lokální MeSH
- hydrofobní a hydrofilní interakce MeSH
- kapronáty chemická syntéza chemie farmakologie MeSH
- kožní absorpce MeSH
- kůže účinky léků MeSH
- kyselina 6-aminokapronová chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- prasata MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- pyrrolidiny chemická syntéza chemie farmakologie MeSH
- simulace molekulární dynamiky MeSH
- stereoizomerie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25μM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.
- MeSH
- aplikace kožní MeSH
- hydrofobní a hydrofilní interakce MeSH
- kapronáty chemie farmakologie MeSH
- kožní absorpce účinky léků MeSH
- molekulární struktura MeSH
- nosiče léků chemie MeSH
- simulace molekulární dynamiky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of substituted 6-aminohexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (logk) was determined. Hydrophobicities (logP/ClogP) of the studied compounds were also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio/DFT calculations of geometry. All the synthesized esters were tested for their in vitro transdermal penetration enhancer activity. The relationships between the lipophilicity and the chemical structure (SLR) of the studied compounds as well as the relationships between their chemical structure and transdermal penetration activity are mentioned.
- MeSH
- aplikace kožní MeSH
- kožní absorpce účinky léků MeSH
- kůže účinky léků metabolismus MeSH
- kyselina 6-aminokapronová chemie farmakologie MeSH
- lipidy chemie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- nosiče léků chemie farmakologie MeSH
- permeabilita účinky léků MeSH
- prasata MeSH
- theofylin aplikace a dávkování farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Experimental and theoretical specific optical rotations (OR) of anhydro, epithio, and epiminoderivatives of methyl tetrofuranosides in chloroform solutions have been compared and used as a tool for exploring their conformational behavior. The potential energy surfaces of these saccharides with reduced flexibility were examined with the density functional theory and the MP2 and CCSD(T) wavefunctions methods. Theoretical ORs were obtained by Boltzmann averaging of values calculated for local minima. Resultant rotations could be used to assess the quality of the DFT and MP2 relative conformer energies. OR values calculated for equilibrium geometries in vacuum were significantly improved when the solvent was accounted for by a polarizable continuum model and first and diagonal second OR derivatives were used for an anharmonic vibrational averaging. The DFT used as a default method reproduced the experimental data fairly well. A modified B3LYP functional containing 70% of HF exchange further improved the results. Because of the strong dependence of OR on the conformation, not only the absolute configuration could be determined, but also the conformational populations were estimated. Likewise, the predicted dependence of OR on the light wavelength well agreed with experiment. The increasing precision of the contemporary computational methods thus makes it possible to relate the specific rotation to more detailed features in molecular structure.
The conditions for the C-N bond forming reaction (C-N coupling reaction) between alpha-bromocarboxylate and nitrogen-containing non-aromatic heterocyclic rings under heterogeneous copper(I) oxide catalysis are investigated in this paper. All the generated compounds were fully characterized by IR, NMR and MS spectroscopy. Ab initio/DFT calculations of partial charges on nitrogen atoms in all the discussed heterocycles and on C((2)) of carboxylate under applied conditions were predicted. These in silico results correlate relatively with the experimental observations.
