Bile Salt–Fatty Acid Mixed Micelles as Nasal Absorption Promoters. III. Effects on Nasal Transport and Enzymatic Degradation of Acyclovir Prodrugs

The absorption enhancement and presystemic degradation kinetics of a homologous series of acyclovir 2-ester prodrugs were investigated in rats using the in situ nasal perfusion technique in the presence of bile salt–fatty acid mixed micells. In vitro incubation studies indicated that nasal perfusate containing a mixed micellar solution generated higher ester-cleaving activity than isotonic phosphate buffer washings. Inhibitor screening and substrate specificity studies demonstrated the enzyme to be most likely carboxylesterase rather than true cholinesterase. The extent of prodrug cleavage by the carboxylesterase appears to correlate well with the substrate li-pophilicity for esters with linear acyl chains. On the other hand, branching of the acyl side chain significantly retards acyclovir pro-drug breakdown. To estimate the nasal epithelial membrane and cytoplasmic damaging effect caused by sodium glycocholate (NaGC)–linoleic acid (15 mM:5 mM) mixed micelles, the release profiles of 5-nucleotidase (5-ND), lactate dehydrogenase (LDH), and carboxylesterase in the nasal perfusate were measured as a function of time. The results indicated that the activities of all three enzymes resulting from the mixed micellar solution appeared to be significantly higher than those caused by 15 mM NaGC alone. The apparent nasal absorption rate constants of acyclovir and its butyrate, valerate, pivalate, and hexanoate ester prodrugs in mixed micellar solutions containing an esterase inhibitor (1 mM phenylmethylsulfonyl fluoride) were individually calculated. Without an inhibitor, lengthening of the linear acyl side chain of the prodrug resulted in greatly accelerated degradation coupled with moderate absorption improvement. The solubilities and micellar binding constants of acyclovir prodrugs were also determined. Mixed micelles composed of 15 mM NaGC and 5 mM linoleic acid are incapable of incorporating these esters into the micellar cavity, although NaGC micelle alone can actively solubilize them in a concentration-dependent manner.     

Polymorphism of Sulfanilamide: (II) Stability Hierarchy of α-, β- and γ- Forms from Energy Calculations by the Atom-Atom Potential Method and from the Construction of the p,T Phase Diagram

Purpose. Sulfanilamide trimorphism was chosen as a model system for comparison between stability hierarchies obtained from lattice-energy calculations with those deduced from the relative locations of the sublimation curves of polymorphs in the sulfanilamide p, T diagram. Methods. The atom-atom potential (AAP) method was used for lattice-energy calculations. The p, T diagram was constructed by using crystallographic and thermodynamic data for α-, β-, and γ- forms, and by assigning the temperatures of the experimentally observed phase transitions to triple points involving the vapour phase. Results. The hierarchy obtained with the AAP method (E_α ≥ E_γ>> E_β) differs only slightly from that deduced from the positions of the sublimation curves (pγ > pα > pβ) in the p, T diagram at room temperature. No stable phase region was found for form α. Thus it is really monotropic. Conclusions. Provided enthalpy and volume changes at the transitions are accurate enough, it is possible to draw a p, T diagram that accounts for the stability hierarchy of polymorphs.     

Denominator changes may obscure results from single-well assays: β3-adrenoceptor ligand-induced changes of cell number as example

Naunyn-Schmiedeberg's Archives of Pharmacology -     

Synthesis and Structure–Activity Relationship Study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as Anticancer Agents

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Synthesis of 6-[1-[4-(benzoxazol-2-yl)thiobuthyl]-1,2,3-triazole-4-yl]methylenepenam as β-lactamase inhibitors

The 6,6-dibromopenam6 was treated with CH₃MgBr and carbaldehyde5 to afford the 6-bromo-6-(1-hydroxy-1-methyl)penicillanate7, which was reacted with acetic anhydride to give acetoxy compound8. The deacetobromination of8 with zinc and acetic acid gave 6-exomethylenpenams, Z-isomer9 and E-isomer10, which were oxidized to sulfones11 and12 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl₃ and neutralized to give the sodium salts13, 14, and15.     

Synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran as a β-amyloid aggregation Inhibitor

An efficient synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran (8), a potent beta-amyloid aggregation inhibitor, is described. 5-Chloro-2-(4-methoxyphenyl)benzofuran (3) was obtained by the one-pot synthesis of 4-chlorophenol with omega-(methylsulfinyl)-p-methoxyacetophenone (1) under Pummerer reaction conditions, and it was followed by the desulfurization of the resultant 5-chloro-3-methylthio-2-(4-methoxyphenyl)benzofuran (2e). Acylation of benzofuran 3 with 4-(3-bromopropoxy)benzoyl chloride (6) gave the ketone 7, which was converted into compound 8 by the treatment of diethylamine.     

Comparison of interactions of R(+)- and S(−)-isomers of β-adrenergic partial agonists,befunolol and carteolol,with high affinity site of β-adrenoceptors in the microsomal fractions from guinea-pig ciliary body,right atria and trachea

• 1.1. The stereoselectivities of β-adrenergic partial agonists for the high affinity binding site of β-adrenoceptors in the guinea-pig ciliary body, right atria and trachea were studied.
• 2.2. The inhibition curves by the S(−)-isomers of befunolol and carteolol were not significantly different from that by the R(+)-isomers in the guinea-pig ciliary body.
• 3.3. The inhibition curves by the S(−)-isomers of befunolol and carteolol were about 10 times as potent as the R(+)-isomers in the guinea-pig atria and trachea.
• 4.4. The pK_i values of the S(−)-isomers of befunolol and carteolol were significantly larger than those of R(+)-isomers in the guinea-pig atria and trachea but not larger than those of the R(+)-isomers in the guinea-pig ciliary body.
• 5.5. These results suggest that the high affinity binding site of β-adrenoceptors in ciliary body cannot discriminate stereoselectively between the R(+)- and S(−)-isomers, while in other tissues there is stereoselectivity between the two enantiomers.

     

Cyclodextrins as carriers for kavalactones in aqueous media: Spectroscopic characterization of (S)-7,8-dihydrokavain and β-cyclodextrin inclusion complex

Kavalactones represent the active constituents of kava–kava (Piper methysticum G. Forster), endowed with sedative and anaesthetic properties. Kavalactones are polar constituents, but poorly soluble in water with a low bioavailability. In this study, the formation of inclusion complexes of one of the most representative kavalactone isolated from kava–kava extract, (S)-7,8-dihydrokavain (DHK), with β-cyclodextrin (β-CyD) was investigated mainly by spectroscopic methods. NMR experiments were extensively used for the complete characterization of the complex and included ¹H NMR complexation shifts analysis, ¹H NMR diffusion measurements (DOSY), and ROESY experiments. In particular DOSY experiments demonstrated that in the presence of β-CyD the translational diffusion of kavalactone is sizably slowed down (2.5 × 10⁻¹⁰ m²/s) with respect to the free drug (4.4 × 10⁻¹⁰ m²/s) according to the inclusion of DHK in the cavity of (β-CyD). ROESY experiments confirmed the inclusion of DHK in the hydrophobic pocket of β-CyD through the primary hydroxyl rim, being the most relevant interactions between the H3′ of β-CyD and the ortho protons on the phenyl ring of the DHK, and between H5′ of β-CyD and the meta/para protons of DHK phenyl ring. The inclusion of the phenyl ring of DHK, leaving the lactone moiety outside of CyD was also confirmed by the induced CD effects. The binary solution DHK/β-CyD shows a 50% intensity increase of the negative band of the π–π* transitions of the phenyl ring with respect to the absorption observed with DHK alone. Molecular dynamics simulations results corroborated and further clarify observed spectroscopic data. It was found that the phenylethyl substituent at C6 has a preferential equatorial position in the free state, and an axial one in the complex, justifying the large downfield shift experienced by H6 of DHK upon binding. Finally the influence of β-CyD on water solubility of DHK was investigated by phase-solubility studies. In the range 2–4 mM of host, solubility of DHK was increased only two-fold, but being β-CyD also a penetration enhancer, in vivo studies will be performed to clarify a possible role of the complex on the bioavailability of DHK.     

Potential anti-cholinesterase and β-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from <Emphasis Type="Italic">Cornus officinalis</Emphasis> fruits

Cholinesterase (ChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer’s disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-β-d-glucose, 1,2,3,6-tetra-O-galloyl-β-d-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1. All of the compounds displayed concentration-dependent in vitro inhibitory activity toward the ChEs and BACE1. Among them, tellimagrandin II exhibited the best inhibitory activity toward ChEs, whereas the best BACE1 inhibitor was 1,2,3,6-tetra-O-galloyl-β-d-glucose. Isoterchebin and polymeric proanthocyanidins were also significant ChE inhibitors. The kinetic and docking studies demonstrated that all compounds interacted with both the catalytic active sites and the peripheral anionic sites of the ChEs and BACE1. Tellimagrandin II, isoterchebin, and the polymeric proanthocyanidins exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. In conclusion, we identified significant ChE and BACE1 inhibitors from Corni Fructus that could have value as new multi-targeted compounds for anti-AD agents.     

Stereoselective synthesis of (<Emphasis Type="Italic">E</Emphasis>)- and (Z)-enol ethers from β-amino aldehydes

Stereocontrolled methods for the direct and divergent synthesis of the silylenol ethers possessing amino group from beta-amino aldehydes have been achieved. These enol ethers with the defined olefin geometry could be key building blocks for the synthesis of the medicinally impor tant compounds.