Complexation of tauro- and glyco-conjugated bile salts with three neutral beta-CDs studied by ACE

Complexation of the bile salts (BS) taurocholate, tauro-beta-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate, and glycochenodeoxycholate common in rat, dog, and man with natural beta-CD and the chemically modified beta-CDs 2-hydroxypropyl-beta-CD and 2-O-methyl-beta-CD was studied using mobility shift ACE. The CDs were selected due to their frequent use in preformulation and drug formulation as oral excipients for the solubilization of drug substances with low aqueous solubility. ACE was demonstrated to be a feasible and efficient technique for investigation of the interactions between BS and beta-CDs. All the investigated BS possessed affinity for the three CDs with stability constants ranging from 2x10(3) to 4x10(5) M(-) (1). The requirements and assumptions related to the use of ACE for estimating high affinity stability constants were discussed. The extent and pattern of hydroxylation significantly influenced the affinity of the glyco- and tauro-conjugated BS toward the beta-CDs (chenodeoxycholates > deoxycholates > cholates) whereas the nature of the beta-CD derivatization and BS conjugation played a minor role only. The results indicate that displacement of drug substances from beta-CD inclusion complexes is likely to occur in the small intestine where BS are present potentially influencing drug bioavailability.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 10³ to 8 × 10⁴ M^?1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.     

Effect of Larger Pore Size on the Sorption Properties of Isoreticular Metal–Organic Frameworks with High Number of Open Metal Sites

Four isostructural CPO-54-M metal-organic frameworks based on the larger organic linker 1,5-dihydroxynaphthalene-2,6-dicarboxylic acid and divalent cations (M=Mn, Mg, Ni, Co) are shown to be isoreticular to the CPO-27 (MOF-74) materials. Desolvated CPO-54-Mn contains a very high concentration of open metal sites, which has a pronounced effect on the gas adsorption of N₂, H₂, CO₂ and CO. Initial isosteric heats of adsorption are significantly higher than for MOFs without open metal sites and are slightly higher than for CPO-27. The plateau of high heat of adsorption decreases earlier in CPO-54-Mn as a function of loading per mole than in CPO-27-Mn. Cluster and periodic density functional theory based calculations of the adsorbate structures and energetics show that the larger adsorption energy at low loadings, when only open metal sites are occupied, is mainly due to larger contribution of dispersive interactions for the materials with the larger, more electron rich bridging ligand.     

Pressing matter: why are ionic liquids so viscous?

Room temperature ionic liquids are considered to have huge potential for practical applications such as batteries. However, their high viscosity presents a significant challenge to their use changing from niche to ubiquitous. The modelling and prediction of viscosity in ionic liquids is the subject of an ongoing debate involving two competing hypotheses: molecular and local mechanisms versus collective and long-range mechanisms. To distinguish between these two theories, we compared an ionic liquid with its uncharged, isoelectronic, isostructural molecular mimic. We measured the viscosity of the molecular mimic at high pressure to emulate the high densities in ionic liquids, which result from the Coulomb interactions in the latter. We were thus able to reveal that the relative contributions of coulombic compaction and the charge network interactions are of similar magnitude. We therefore suggest that the optimisation of the viscosity in room temperature ionic liquids must follow a dual approach.

We use an experimental approach to compare an ionic liquid with a molecular mimic, focusing on viscosities. Charge network and coulombic compaction contribute significantly to the high viscosity of ionic liquids; we discuss the implications on their design and optimisation.