Technical Procedures for the Syntheses of Carotenoids and Related Compounds from 6-Oxo-isophorone: Syntheses of (3R,3′R)-Zeaxanthin. Part II

Starting from the readily available, optically active (4R)-hydroxy-2,2,6-trimethylcyclohexanone ( 2 ), a new technical synthesis of (3R,3′R)-zeaxanthin is described. According to a completely new C₉+C₂+C₄ = C₁₅ scheme, the ketone 2 was protected, ethynylated with Li-acetylide, and the C₁₁-intermediate 6 was acetylated, followed by dehydration. The product 10 was protected, deprotonated, and subsequently reacted with methyl vinyl ketone to provide the C₁₅-propargylate 13 . Reduction in situ of 13 with Vitride yielded the olefinic C₁₅-alcohol 11 which was transformed into the known C₁₅-Wittig salt 3 . A double Wittig reaction of this salt with the C₁₀-dialdehyde 4 afforded nature-identical zeaxanthin ( 1 ).     

Resolvability and monotone normality

A space X is said to be κ-resolvable (resp., almost κ-resolvable) if it contains κ dense sets that are pairwise disjoint (resp., almost disjoint over the ideal of nowhere dense subsets). X is maximally resolvable if and only if it is Δ(X)-resolvable, where Δ(X) = min{|G| : G ≠ open}. We show that every crowded monotonically normal (in short: MN) space is ω-resolvable and almost μ-resolvable, where μ = min{2 ^ω , ω ₂}. On the other hand, if κ is a measurable cardinal then there is a MN space X with Δ(X) = κ such that no subspace of X is ω ₁-resolvable. Any MN space of cardinality < ℵ _ω is maximally resolvable. But from a supercompact cardinal we obtain the consistency of the existence of a MN space X with |X| = Δ(X) = ℵ _ω such that no subspace of X is ω ₂-resolvable. The preparation of this paper was supported by OTKA grant no. 61600     

On the weak Freese-Nation property of complete Boolean algebras

The following results are proved:

(a) In a model obtained by adding ₂ Cohen reals, there is always a c.c.c. complete Boolean algebra without the weak Freese-Nation property. (b) Modulo the consistency strength of a supercompact cardinal, the existence of a c.c.c. complete Boolean algebra without the weak Freese-Nation property is consistent with GCH. (c) If a weak form of □_μ and cof([μ]^₀,)=μ⁺ hold for each μ>cf(μ)=ω, then the weak Freese-Nation property of is equivalent to the weak Freese-Nation property of any of or for uncountable κ. (d) Modulo the consistency of (_ω+1,_ω)(₁,₀), it is consistent with GCH that does not have the weak Freese-Nation property and hence the assertion in (c) does not hold, and also that adding _ω Cohen reals destroys the weak Freese-Nation property of .

These results solve all of the problems except Problem 1 in S. Fuchino, L. Soukup, Fundament. Math. 154 (1997) 159–176, and some other problems posed by Geschke.     

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC₅₀(AChE) = 2.9–1.4 µM, IC₅₀(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ₄₂ aggregation. Conjugates 3 had no effect on Aβ₄₂ self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.     

Development and validation of an efficient HPLC method for quantification of voriconazole in plasma and microdialysate reflecting an important target site

Voriconazole is a very potent antifungal agent used to treat serious fungal infections (candidiasis); it is also the therapy of choice for aspergillosis. After standard dosing, several factors affect exposure of voriconazole, resulting in large variability and demanding further elucidation of drug distribution. For measurements at the site of action, microdialysis is considered to be an outstanding minimally invasive method. For determination of voriconazole in microdialysate and human plasma a new, efficient, reliable, and robust HPLC assay using UV detection at 254 nm has been developed and validated. After simple sample preparation using acetonitrile for plasma and for microdialysate, 20 μL were injected and separated on an RP-18 column. The chromatographic run time was less than 4 min. Overall, the assay showed high precision (CV 93.9 to 99.5%) and accuracy (RE −96.7 to +107%) for both matrices. Of the 36 drug products typically co-administered with voriconazole, none except ambroxol interfered with its peak signal, and this interference was successfully managed. In summary, the method is highly suitable for application in (pre)clinical microdialysis studies, e.g., of critically ill patients with invasive mycoses. Figure Microdialysis probe situated in the interstitial space fluid containing voriconazole drug molecules (magenta coloured) extracting an important target site representative matrix (microdialysate) [Courtesy of CMA]     

Underground coal gasification: rates of post processing gas transport

Two ex-situ and one in-situ semi-pilot plant UCG experiments in the experimental mine Barbara were performed with hard coal and lignite samples. To evaluate the influence of the UCG process on the textural properties of surrounding strata and coals, samples from various locations of the coal seam and the stratum samples before and after the UCG process were collected. Mercury porosimetry, helium pycnometry, and physical adsorption of nitrogen were used for the determination of textural properties of samples. Permeation gas transport was modelled based on the knowledge of the real structure characteristics of the stratum samples by the Mean Transport-Pore Model (MTPM). Influence of the individual texture and transport parameters on the post processing gas transport through porous strata with respect to the variability of their possible values was also evaluated.     

Sorption of inorganic nanoparticles in woven cellulose fabrics

Titanium dioxide was deposited from aqueous suspension onto cellulosic surfaces.Titania was sourced from Degussa (P25TM,70:30 anatase:rutile).Dry uptake of particles was shown to be rapid and dominant with one-third of the deposition occurring in less than 30 s and over one-half in the first minute.Isotherms were recorded to compare the rate of titanium deposition on dry and pre-wetted cotton.In the dry case uptake reached a maximum in 30 min whereas in the pre-wetted case the uptake was seen to continue beyond 180 min.A broad trend of higher deposition occurring at lower pH was seen,corresponding to the region where surface charges were opposite and thus attractive.Dry pickup was less significant at high pH.The response to varying ionic strength was complex and was attributed to the combined effect of charge screening,particle aggregation and consequent particle entrapment or occlusion.Titania deposition into the interstices of woven cotton sheets resulted in the formation of inorganic,nanoparticulate skeletons which could be isolated by controlled combustion of the cellulose and thus cotton was suggested to have potential for the templated synthesis of high surface area semiconductor materials.     

Essentially disjoint families, conflict free colorings and Shelah’s revised GCH

Using Shelah’s revised GCH theorem we prove that if μ<? _ω ≦λ are cardinals, then every μ-almost disjoint family ${\mathcal{A}}\subset {[\lambda]}^{\beth_{\omega}}$ is essentially disjoint, i.e. for each ${A\in {\mathcal{A}}}$ there is a set F(A)∈[A]^<|A| such that the family $\{{A\setminus F(A)}: {A\in {\mathcal{A}}}\}$ is disjoint. We also show that if μ≦κ≦λ are cardinals, κ≧ω, and

• every μ-almost disjoint family ${\mathcal{A}}\subset {[\lambda]}^{{\kappa}}$ is essentially disjoint,

then

• every μ-almost disjoint family ${\mathcal {B}}\subset {[\lambda]}^{\geqq {\kappa}}$ has a conflict-free coloring with κ colors, i.e. there is a coloring f:λ→κ such that for all ${B\in {\mathcal{B}}}$ there is a color ξ<κ such that |{β∈B:f(β)=ξ}|=1.

Putting together these results we obtain that if μ<? _ω ≦λ, then every μ-almost disjoint family ${{\mathcal{B}}\subset {[\lambda]}^{\geqq \beth_{\omega}}}$ has a conflict-free coloring with ? _ω colors. To yield the above mentioned results we also need to prove a certain compactness theorem concerning singular cardinals.     

Reversal of diastereofacial selectivity in hydride reductions of N-tert-butanesulfinyl imines

A variety of N-tert-butanesulfinyl imines were reduced with NaBH4 in THF containing 2% water to provide the corresponding secondary sulfinamides in high yield and diastereoselectivity. By using the same sulfinyl imine starting materials and changing the reductant to L-Selectride, the stereoselectivity could be efficiently reversed to afford the opposite product diastereomer in high yield and selectivity.