La presente invention a pour objet un compose de formule ( I ) ; ses formes cristallines, et ses ... more La presente invention a pour objet un compose de formule ( I ) ; ses formes cristallines, et ses solvates ; des compositions pharmaceutiques comprenant une quantite pharmaceutiquement efficace du compose de formule ( I ), ou d'une forme cristalline de celui-ci, ou d'un solvate de celui-ci, et un support ou un diluant pharmaceutiquement acceptable ; et l'utilisation d'un compose de formule ( I ), ou d'une forme cristalline de celui-ci, ou d'un solvate de celui-ci, pour le traitement d'un patient souffrant d'un etat pathologique, ou sujet a un etat pathologique capable d'etre ameliore par l'inhibition d'une enzyme d'activation E1, en particulier la NAE, comprenant, par exemple, le cancer.
Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of m... more Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of different amorphous carbohydrates (glucose, sucrose, and trehalose) as a function of temperature. Plots of specific volume vs temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state. The intersection of the regression lines of data below (glassy state) and above (rubbery state) the change in slope provides the glass transition temperature (T g). These predicted glass transition temperatures are compared to experimental T g values as obtained from differential scanning calorimetry measurements. As expected, the predicted values are systematically higher than the experimental ones (about 12-34 K) as the cooling rates of the modeling methods are about a factor of 10 12 faster. Nevertheless, the calculated trend of T g values agrees exactly with the experimental trend: T g glucose < T g sucrose < T g trehalose. Furthermore, the relative differences between the glass transition temperatures were also computed precisely, implying that atomistic molecular dynamics simulations can reproduce trends of T g values in amorphous carbohydrates with high quality.
The lactonisation of a CCR1 inhibitor (CC chemokine receptor 1, involved in autoimmune diseases) ... more The lactonisation of a CCR1 inhibitor (CC chemokine receptor 1, involved in autoimmune diseases) featuring a hydroxyl group in a gamma-position (gamma-OH) with respect to an amide group has been investigated in silico. The two key steps of the lactonisation reaction are (i) rearrangement to an optimal conformation and (ii) the formation of the lactone (ring closure) and expulsion of NH3. Quantum chemical calculations in the gas phase were employed to identify conformers of the molecule with favorable starting geometries for a lactonisation reaction. In total, calculations of 1296 conformers revealed that it is energetically feasible for an inhibitor molecule to adopt a conformation where the carbon atom of the amide group (C(amide)) is suitably close to the oxygen atom of the gamma-OH (O(gamma)) to facilitate a successful lactonisation reaction. Additionally, molecular dynamics methods were used to show that rearrangement to a suitable conformer for lactonisation to occur happens to a lesser extent when the CCR1 inhibitor was embedded in an amorphous trehalose matrix (a model carbohydrate excipient). The mechanism of the actual lactonisation was investigated using the complete Linear Synchronous Transit/Quadratic Synchronous Transit (LST/QST) method. This was performed in both the gas phase and in water and was found to be a concerted reaction.
Nanorods of nickel and copper oxalate have been synthesized by the reverse micellar route. Powder... more Nanorods of nickel and copper oxalate have been synthesized by the reverse micellar route. Powder X-ray diffraction studies and thermo gravimetric analysis confirms the formation of monophasic NiC2O4 x 2H2O and CuC2O4 x H2O. Transmission electron microscopy shows that the as prepared nanorods of nickel and copper have diameter of 250 nm and 130 nm while the length is of the order of 2.5 microm and 480 nm respectively. The aspect ratio of the nanorods could be modified by changing the solvent. The nickel oxalate nanorods appear very smooth with uniform length while the copper oxalate nanorods appear to be corrugated. Nickel oxalate dihydrate nanorods show an antiferromagnetic transition at T(N) = 34 K while the copper based nanorods show temperature independent paramagnetism.
Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of m... more Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of trehalose and three amorphous trehalose-water mixtures (2.9%, 4.5% and 5.3% (w/w) water, respectively) as a function of temperature. Plots of specific volume versus temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state and the intersection of the two regression lines provides an estimate of the glass transition temperature T g. A comparison of the calculated and experimental T g values, as obtained from differential scanning calorimetry, shows that despite the predicted values being systematically higher (about 21-26 K), the trend and the incremental differences between the T g values have been computed correctly: T 5:3% ðw=wÞ g < T 4:5% ðw=wÞ g < T 2:9% ðw=wÞ g < T 0:0% ðw=wÞ g. The mobility of water has been investigated over temperature ranges covering the rubbery and the glassy phases of the trehalose-water mixtures by calculating the diffusion coefficients of water. The temperature dependence of the diffusion coefficient changes in the region of the glass transition and can be used as well to estimate T g values. The activation energies for water diffusion were found to be independent of the amount of water in amorphous trehalose.
La presente invention a pour objet un compose de formule ( I ) ; ses formes cristallines, et ses ... more La presente invention a pour objet un compose de formule ( I ) ; ses formes cristallines, et ses solvates ; des compositions pharmaceutiques comprenant une quantite pharmaceutiquement efficace du compose de formule ( I ), ou d'une forme cristalline de celui-ci, ou d'un solvate de celui-ci, et un support ou un diluant pharmaceutiquement acceptable ; et l'utilisation d'un compose de formule ( I ), ou d'une forme cristalline de celui-ci, ou d'un solvate de celui-ci, pour le traitement d'un patient souffrant d'un etat pathologique, ou sujet a un etat pathologique capable d'etre ameliore par l'inhibition d'une enzyme d'activation E1, en particulier la NAE, comprenant, par exemple, le cancer.
Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of m... more Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of different amorphous carbohydrates (glucose, sucrose, and trehalose) as a function of temperature. Plots of specific volume vs temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state. The intersection of the regression lines of data below (glassy state) and above (rubbery state) the change in slope provides the glass transition temperature (T g). These predicted glass transition temperatures are compared to experimental T g values as obtained from differential scanning calorimetry measurements. As expected, the predicted values are systematically higher than the experimental ones (about 12-34 K) as the cooling rates of the modeling methods are about a factor of 10 12 faster. Nevertheless, the calculated trend of T g values agrees exactly with the experimental trend: T g glucose < T g sucrose < T g trehalose. Furthermore, the relative differences between the glass transition temperatures were also computed precisely, implying that atomistic molecular dynamics simulations can reproduce trends of T g values in amorphous carbohydrates with high quality.
The lactonisation of a CCR1 inhibitor (CC chemokine receptor 1, involved in autoimmune diseases) ... more The lactonisation of a CCR1 inhibitor (CC chemokine receptor 1, involved in autoimmune diseases) featuring a hydroxyl group in a gamma-position (gamma-OH) with respect to an amide group has been investigated in silico. The two key steps of the lactonisation reaction are (i) rearrangement to an optimal conformation and (ii) the formation of the lactone (ring closure) and expulsion of NH3. Quantum chemical calculations in the gas phase were employed to identify conformers of the molecule with favorable starting geometries for a lactonisation reaction. In total, calculations of 1296 conformers revealed that it is energetically feasible for an inhibitor molecule to adopt a conformation where the carbon atom of the amide group (C(amide)) is suitably close to the oxygen atom of the gamma-OH (O(gamma)) to facilitate a successful lactonisation reaction. Additionally, molecular dynamics methods were used to show that rearrangement to a suitable conformer for lactonisation to occur happens to a lesser extent when the CCR1 inhibitor was embedded in an amorphous trehalose matrix (a model carbohydrate excipient). The mechanism of the actual lactonisation was investigated using the complete Linear Synchronous Transit/Quadratic Synchronous Transit (LST/QST) method. This was performed in both the gas phase and in water and was found to be a concerted reaction.
Nanorods of nickel and copper oxalate have been synthesized by the reverse micellar route. Powder... more Nanorods of nickel and copper oxalate have been synthesized by the reverse micellar route. Powder X-ray diffraction studies and thermo gravimetric analysis confirms the formation of monophasic NiC2O4 x 2H2O and CuC2O4 x H2O. Transmission electron microscopy shows that the as prepared nanorods of nickel and copper have diameter of 250 nm and 130 nm while the length is of the order of 2.5 microm and 480 nm respectively. The aspect ratio of the nanorods could be modified by changing the solvent. The nickel oxalate nanorods appear very smooth with uniform length while the copper oxalate nanorods appear to be corrugated. Nickel oxalate dihydrate nanorods show an antiferromagnetic transition at T(N) = 34 K while the copper based nanorods show temperature independent paramagnetism.
Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of m... more Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of trehalose and three amorphous trehalose-water mixtures (2.9%, 4.5% and 5.3% (w/w) water, respectively) as a function of temperature. Plots of specific volume versus temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state and the intersection of the two regression lines provides an estimate of the glass transition temperature T g. A comparison of the calculated and experimental T g values, as obtained from differential scanning calorimetry, shows that despite the predicted values being systematically higher (about 21-26 K), the trend and the incremental differences between the T g values have been computed correctly: T 5:3% ðw=wÞ g < T 4:5% ðw=wÞ g < T 2:9% ðw=wÞ g < T 0:0% ðw=wÞ g. The mobility of water has been investigated over temperature ranges covering the rubbery and the glassy phases of the trehalose-water mixtures by calculating the diffusion coefficients of water. The temperature dependence of the diffusion coefficient changes in the region of the glass transition and can be used as well to estimate T g values. The activation energies for water diffusion were found to be independent of the amount of water in amorphous trehalose.
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