Remote modulation of amine basicity by a phenylsulfone and a phenylthio group.
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Amines↗
Biomedical subjects
Stefanie Bendels
Publications and source records attributed to Stefanie Bendels.
PAMPA - excipient classification gradient map.
The effect of excipients on the artificial membrane permeability (Double-Sink PAMPA) properties of eight sparingly soluble drugs was studied. Quantities of excipient were selected to match the concentrations expected in the gastrointestinal fluid under clinically relevant conditions. Over 1,200 measurements were performed. To correct for the effects of the aqueous boundary layer and determine the intrinsic permeability, precisely measured ionization constants were used. The intrinsic permeability of weak acids was enhanced (up to 100 fold) but that of weak bases depressed (up to 270 fold) by the excipients: mefenamic acid > glybenclamide > progesterone > griseofulvin > clotrimazole > astemizole > dipyridamole > butacaine. Excipient enhancement ranked: 3 mM NaTC > 0.24% PEG400 > 0.2 M KCl > 0.24% NMP > 5% PEG400 > 0.24% PG > 1% PEG400 > 0.1M KCl > 1% PG > 1% NMP > 5% PG > 0.24% HP-beta-CD > 1% HP-beta-CD > 15 mM NaTC. The study clearly indicates that the method is suitable for use in preclinical development to assess the effect of excipients on the permeability of sparingly soluble drug candidates. The method is quick, cost-effective, and reasonably accurate. The self-rank-ordered PAMPA-Mapping may be a helpful visualization tool for delivery screening.
Cell Membrane Permeability↗
Fluorine in medicinal chemistry.
Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.
Fluorine↗
Comparison of a 3D-model of the classical alpha-scorpion toxin V from Leiurus quinquestriatus quinquestriatus with other scorpion toxins.
In the present paper, a study of classical and insect alpha-scorpion toxins is described. A homology model of the classical alpha-toxin LqqV from Leiurus quinquestriatus quinquestriatus was developed. The model was compared to stable and energetically favourable conformations of AaHII from Androctonus australis Hector and LqhalphaIT from Leiurus quinquestriatus hebraeus, which are the most active alpha-toxins in mammals and insects. The conformations were retrieved from molecular dynamics simulations of known structures. The model of LqqV shows a C-terminal conformation similar to LqhalphaIT. This is mainly caused by electrostatic interactions between Lys10 /Lys60 and Glu59, which are comparable to the cation-pi interactions of Tyr10 and Arg64 in LqhalphaIT. During the simulations the structures of AaHII and LqqV were stabilised through electrostatic interactions between Glu32 and Lys50 and especially the loop adjacent to the alpha-helix is affected, which is in contrast to LqhalphaIT. When the molecular electrostatic potentials of the toxins were studied, a possibly important difference between the classical alpha-toxins and the insect alpha-toxin LqhalphaIT was found in the area around Lys30 and Arg56 of AaHII, where a positive potential is missing in LqhalphaIT. A large negative potential caused by Asp3, Glu15 and Asp19 in LqhalphaIT is also unique for this toxin. It is proposed that Arg18, which is important for activity of LqhalphaIT, restricts the negative potential in this area and is not essential for toxins where negatively charged residues in comparable positions are not present.
Amino Acid Sequence↗