Application of the 2-deoxyglucose scaffold as a new chiral probe for elucidation of the absolute configuration of secondary alcohols.

Herein, we present the application of 2-deoxy-D-glucose derivatives as chiral probes for elucidation of the absolute configuration of chiral secondary alcohols. The probes are attached to the studied molecules via glycosylation reaction and the resulting products are examined by a set of standard 2D NMR experiments. The absolute configuration of an oxymethine carbon atom binding the probe is established on a basis of a set of diagnostic dipolar couplings (NOEs/ROEs). These correlations may be considered diagnostic due to a pronounced lack of conformational freedom of the formed glycosidic linkage. While the chance for an observation of the diagnostic signals is the highest when the resulting glycoside in an α-anomer. 2-deoxy-D-glucose was selected as a probe of choice since is it known to strongly prefer the formation of α-glycosides.

Acid-Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis.

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic transformations in vitro and in tumor cells. However, the physicochemical properties of UAs, which could possibly affect their interactions with molecular targets, remain unknown. Therefore, we selected four highly active UAs for the assessment of physicochemical parameters under various pH conditions. We determined the compounds' pKa dissociation constants as well as their potential to self-associate. Both parameters were determined by detailed and complex chemometric analysis of UV-Vis spectra supported by nuclear magnetic resonance (NMR) spectroscopy. The obtained results indicate that general molecular properties of UAs in aqueous media, including their protonation state, self-association ratio, and solubility, are strongly pH-dependent, particularly in the physiological pH range of 6 to 8. In conclusion, we describe the detailed physicochemical characteristics of UAs, which might contribute to their selectivity towards tumour cells as opposed to their effect on normal cells.

Products of Photo- and Thermochemical Rearrangement of 19-Membered di-tert-Butyl-Azoxybenzocrown.

The preparation and characterization of products of the photochemical and thermochemical rearrangements of 19-membered azoxybenzocrowns with two, bulky, tert-butyl substituents in benzene rings in the para positions to oligooxyethylene fragments (meta positions to azoxy group, i.e., t-Bu-19-Azo-O have been presented. In photochemical rearrangement, two colored typical products were expected, i.e., 19-membered o-hydroxy-m,m'-di-tert-butyl-azobenzocrown (t-Bu-19-o-OH) and 19-membered p-hydroxy-m,m'-di-tert-butyl-azobenzocrown (t-Bu-19-p-OH). In experiments, two colored atypical macrocyclic derivatives, one 6-membered and one 5-membered ring, bearing an aldehyde group (t-Bu-19-al) or intramolecular ester group (t-Bu-20-ester), were obtained. Photochemical rearrangement led to one more macrocyclic product being isolated and identified: a 17-membered colorless compound, without an azo moiety, t-Bu-17-p-OH. The yield of the individual compounds was significantly influenced by the reaction conditions. Thermochemical rearrangement led to t-Bu-20-ester as the main product. The structures of the four crystalline products of the rearrangement-t-Bu-19-o-OH, t-Bu-19-p-OH, t-Bu-20-ester and t-Bu-17-p-OH-were determined by the X-ray method. Structures in solution of atypical derivatives (t-Bu-19-al and t-Bu-20-ester) and t-Bu-19-p-OH were defined using NMR spectroscopy. For the newly obtained hydroxyazobenzocrowns, the azo-phenol⇄quinone-hydrazone tautomeric equilibrium was investigated using spectroscopic methods. Complexation studies of alkali and alkaline earth metal cations were studied using UV-Vis absorption spectroscopy. 1H NMR spectroscopy was additionally used to study the cation recognition of metal cations. Cation binding studies in acetonitrile have shown high selectivity towards calcium over magnesium for t-Bu-19-o-OH.

Effect of chemical structure on complexation efficiency of aromatic drugs with cyclodextrins: The example of dibenzazepine derivatives.

It is widely believed that the hydrophobic effect governs the binding of guest molecules to cyclodextrins (CDs). However, it is also known that high hydrophobicity of guest molecules does not always translate to the formation of stable inclusion complexes with CDs. Indeed, a plethora of other factors can play a role in the efficiency of guest-CD interactions, rendering structure-based prediction of the complexation efficiency with CDs a non trivial task. In this combined experimental and computational study, we examine the major structural factors governing complexation efficiency of polycyclic aromatic drug-like compounds with natural CDs, using as an example iminostilbene and its N-substituted derivatives. We find that purely hydrophobic IS derivatives show negligible complexation efficiency with CDs and only IS with hydrophilic substituents form stable inclusion complexes in water. We show that the balance between the guest solubility and its affinity to CDs is critical for the effective formation of inclusion complexes. Finally, our results demonstrate that guest-host hydrogen bonds facilitate the formation of crystalline inclusion complexes with CDs.

Photochemical Rearrangement of a 19-Membered Azoxybenzocrown: Products and their Properties.

The preparation and characterization of products of the chemical and photochemical rearrangements of a 19-membered o,o'-azoxybenzocrown are presented. In photochemical rearrangement, besides the expected product i. e. 19-membered o-hydroxy-o,o'-azobenzocrown (19-o-OH) obtained under defined conditions with 75 % yield, also other macrocyclic products were isolated and identified, namely: 19-membered p-hydroxy-o,o'-azobenzocrown (19-p-OH), 21-membered o'-hydroxy-o,p'-azobenzocrown (21-o'-OH) and 19-membered macrocycle containing a 5-membered ring bearing an aldehyde group (19-al). The structures of two atypical products of the photochemical rearrangement - 21-o'-OH and 19-al - were determined in the solid state by X-ray analysis and in solution using NMR spectroscopy. Tautomeric equilibrium of the formed hydroxyazobenzocrowns and its change depending on acidity/basicity of the environment and alkali and alkaline earth metal cations complexation were studied using UV-Vis spectrophotometry, spectrofluorimetry and 1 H NMR spectroscopy.

The complete stereochemistry of the antibiotic candicidin A3 (syn. ascosin A3, levorin A3).

Herein, the stereostructure of the aromatic heptaene macrolide (AHM) antifungal antibiotic candicidin A3 (syn. ascosin A3, levorin A3) has been established upon the 2D NMR studies, consisting of DQF-COSY, TOCSY, ROESY, HSQC and HMBC experiments, as well as upon extensive molecular dynamics simulations. The geometry of the heptaenic chromophore was defined as: (22E, 24E, 26Z, 28Z, 30E, 32E, 34E). The previously unreported absolute configuration of the chiral centres of candicidin A3 was established as: (3R, 9R, 11S, 13S, 15R, 17S, 18R, 19S, 21R, 36S, 37R, 38S, 40S, 41S).