Biodegradable polymeric prodrugs of naltrexone

The development of a biodegradable polymeric drug delivery system for the narcotic antagonist naltrexone may improve patient compliance in the treatment of opiate addiction. Random copolymers consisting of the ¿-amino acids N5-(3-hydroxypropyl--glutamine and -leucine were synthesized with equimolar initial monomer feeds. The molecular weight of this chemical carrier was determined by viscometry and wide-angle light scattering. In order to get selective covalent coupling of drug to polymer the 3-acetate derivative and the 14-acetate derivative of naltrexone were synthesized and characterized by NMR. Hydrolytic conversion of each monoacetate to parent drug was monitored by HPLC and the rate constant was determined. Both derivatives were coupled via hydrolytically labile carbonate linkages to the polymer hydroxyl groups. The drug conjugates were prepared as particles of various size ranges between 20 and 350 ¿. In vitro studies in phosphate-buffered saline (pH 7.4) demonstrated a release rate dependence on particle size. Nearly constant plasma levels of naltrexone were obtained for one month after subcutaneous injection in rats

The Betulin Project: Introduction 2014

CH 203 Betulin Project Lab. Introduction to the Betulin Project

Synthesis of several bisabolane sesquiterpenoids from xanthorrhizol isolated from C. Xanthorrhiza

Xanthorrhizol was isolated from the essential oil of fresh rhizomes of C. xanthorrhiza in 20.2% yield by fractionation using vacuum liquid chromatography. Several bisabolane-type sesquiterpenoids have been synthesised from this xanthorrhizol. Both diastereomers of 10,11-dihydro-10,11-dihydroxyxanthorrhizols, sesquiterpenoids isolated from the Mexican medicinal plant, Iostephane heterophylla, have been prepared in three steps from xanthorrhizol via Sharpless asymmetric dihydroxylation as the key steps. Fremy’s salt oxidation of xanthorrhizol gave curcuhydroquinone in 60% yield, which was successfully reduced with sodium dithionite to curcuhydroquinone in 100% yield. Sequential acetylation and Sharpless asymmetric dihydroxylation on curcuhydroquinone led to the diacetate derivative of helibisabonol A. Cleavage of the diacetate esters by reduction with lithium borohydride furnished helibisabonol A, an allelopathic agent isolated from Helianthus annuus (sunflowers). The unexpected difficulty in deprotection of helibisabonol A diacetate was due to acidic, basic and air-sensitive natures of helibisabonol A. An allylic alcohol derivative of O-methylxanthorrhizol, (3S,6R)-(3- methoxy-4-methylphenyl)-2-methylhept-1-en-3-ol, has been synthesised from xanthorrhizol in five steps via Sharpless asymmetric dihydroxylation as the key steps. Sharpless asymmetric dihydroxylation in all syntheses gave excellent enantioselectivity (ee > 98%). The enantiomeric excess and the absolute configuration of the diol was determined by the modified Mosher’s method

Chemoenzymatic Synthesis of Chiral 1-Benzyl-5-(hydroxymethyl)- 2-piperidone Enabled by Lipase AK-Mediated Desymmetrization of Prochiral 1,3-Diol and Its Diacetate

The synthesis of (R)-1-benzyl-5-(hydroxymethyl)-2-piperidone (1) from key synthon monoacetate (R)-3 has been accomplished conveniently in 6 steps with 93 % ee and in 44 % overall yield. The key step involved lipase AK-mediated desymmetrization of diol 4 to produce monoacetate (R)-3 in 93 % ee and 93 % yield. Additionally, lipase AK-mediated desymmetrization of diacetate 5 readily provided access to monoacetate (S)-3 in 93 % ee and 54 % yield

Vitamin C inhibits endothelial cell apoptosis in congestive heart failure

Background - Proinflammatory cytokines like tumor necrosis factor- and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients. Methods and Results - Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor- and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32±8% of baseline levels, whereas placebo had no effect (87±14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001). Conclusions - Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function

Alkaloids, Coumarins and Lignans from Haplophyllum Species

Although there are a number of Haplophyllum species in the world, H. acutifolium (DC.) G. Don, H. buxbaumii (Poiret) G.Don, H. buxbaumii (Poiret) G.Don, subsp. Buxbaumii, H. cappadocium Spach, H. glabrinum, H. hispanicum Sprach, H. myrtifolium Boiss., H. patavinum (L.) G. D. ON. fil., H. perforatum (M.B.) Vved., H. ptilostylum Spach, H. suaveolens (DC.) G.Don, H. telephioides Boiss., H. thesioides (Fisch ex DC.) G. Don, H. tuberculatum (Forssk.) A.Juss. and H. vulcanicum Boiss. & Heldr. were most studied and a lot of compounds isolated. Only alkaloids, coumarins and lignans of these species are mentioned in this article. In addition some volatile components of H. tuberculatum were also give

A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer

In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2 and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions