Solubilization of itraconazole as a function of cyclodextrin structural space

Cyclodextrins are functional pharmaceutical excipients, which can dynamically include poorly water-soluble drugs and drug candidates resulting in improved solubility, stability and oral bioavailability. A number of formulations containing “natural” and chemically modified cyclodextrins have reached the market and are enjoying widespread attention and use. One such example is itraconazole, a broad-spectrum antifungal agent which is available in an aqueous hydroxypropyl-β-cyclodextrin (HPβCD) vehicle for both oral and parenteral use (Sporanox Oral Solution and Sporanox Intravenous Injection^®). While the interaction of itraconazole and HPβCD is well described, its ability to form complexes with other cyclodextrins is less understood. This creates an intriguing opportunity of screening the structural space of available cyclodextrin derivates by assessing their complexation with a single chemical probe, in this case itraconazole. To this end, a number of cyclodextrin derivatives were assess with regard to their ability to improve the water solubility of the test substrate. In some instances, more detail assessments including the effect of pH and the physical form of the drug probe were also completed. The various cyclodextrins solubilized itraconazole to varying extents (micrograms to milligrams) and by varying inclusion mechanisms and stoichiometries.     

Enantiopure bicyclic piperidinones: stereocontrolled conjugate additions leading to substituted piperidinones

The conjugate additions of Reformatsky reagents, organocuprate reagents, and hydroxylamines to a [4.3.0]-bicyclic enelactam derived from 6-oxopipecolic acid have been investigated, and found to be efficient, proceeding with excellent exo-stereocontrol, with the exception of N-benzyl-O-benzylhydroxylamine, which gives predominantly the product of endo-addition. These adducts can be readily converted to substituted piperidinones.     

Protein encapsulation: a new approach for improving the capability of small-molecule fluorogenic probes

Herein, we report a protein-based hybridization strategy that exploits the host-guest chemistry of HSA (human serum albumin) to solubilize the otherwise cell impermeable ONOO⁻ fluorescent probe Pinkment-OAc. Formation of a HSA/Pinkment-OAc supramolecular hybrid was confirmed by SAXS and solution-state analyses. This HSA/Pinkment-OAc hybrid provided an enhanced fluorescence response towards ONOO⁻versusPinkment-OAc alone, as determined by in vitro experiments. The HSA/Pinkment-OAc hybrid was also evaluated in RAW 264.7 macrophages and HeLa cancer cell lines, which displayed an enhanced cell permeability enabling the detection of SIN-1 and LPS generated ONOO⁻ and the in vivo imaging of acute inflammation in LPS-treated mice. A remarkable 5.6 fold (RAW 264.7), 8.7-fold (HeLa) and 2.7-fold increased response was seen relative to Pinkment-OAc alone at the cellular level and in vivo, respectively. We anticipate that HSA/fluorescent probe hybrids will soon become ubiquitous and routinely applied to overcome solubility issues associated with hydrophobic fluorescent imaging agents designed to detect disease related biomarkers.

Herein, we report a protein-based hybridization strategy that exploits the host–guest chemistry of HSA (human serum albumin) to solubilize the otherwise cell impermeable ONOO⁻ fluorescent probe Pinkment-OAc.     

Self‐Assembly of Disorazole C1 through a One‐Pot Alkyne Metathesis Homodimerization Strategy

Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne‐metathesis‐based homodimerization approach to natural products. In this approach to the cytotoxic C₂‐symmetric marine‐derived bis(lactone) disorazole C₁, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one‐pot alkyne cross‐metathesis/ring‐closing metathesis self‐assembly process.     

Graph homomorphism reconfiguration and frozen H-colorings

We say that a graph $F$ strongly arrows a pair of graphs $\left(G,H\right)$ and write $\text{◂→▸}F\stackrel{\text{ind}}{\to }\left(G,H\right)$ if any coloring of its edges with red and blue leads to either a red $G$ or a blue $H$ appearing as induced subgraphs of $F$. The induced Ramsey number, $\text{◂...▸}\text{IR}\left(G,H\right)$, is defined as $\text{◂lim▸}\min \text{◂{}▸}\{|V\left(F\right)|:\text{◂→▸}F\stackrel{\text{ind}}{\to }\left(G,H\right)\}$. We consider the connection between the induced Ramsey number for a pair of two connected graphs $\text{◂...▸}\text{IR}\left(G,H\right)$ and the induced Ramsey number for multiple copies of these graphs $\text{IR}\text{◂()▸}\left(sG,tH\right)$, where $xG$ denotes the pairwise vertex-disjoint union of $x$ copies of $G$. It is easy to see that if $\text{◂→▸}F\stackrel{\text{ind}}{\to }\left(G,H\right)$, then $\text{◂⋅▸}\left(s+t-1\right)F\stackrel{\text{ind}}{\to }\text{◂()▸}\left(sG,tH\right)$. This implies that $$\text{◂...▸}\text{IR}\text{◂≤▸}\text{◂()▸}\left(sG,tH\right)\le \left(s+t-1\right)\text{IR}\left(G,H\right).$$ For several specific graphs, such as a path on three vertices vs a complete multipartite graph, a matching vs a complete graph, or a matching vs another matching, it is known that the above inequality is tight. On the other hand, the inequality is also strict for some graphs. However, even in the simplest case when $H$ is an edge and $t=2$, it is not known for what $G$ and for what $s$ the above inequality is tight. We show that it is tight if $G$ is connected and $s$ is at least as large as the order of $G$. In addition, we make further progress in determining induced Ramsey numbers for multiple copies of graphs, such as paths and triangles.     

Building blocks for the variety of absolute retracts

Given a graph H with a labelled subgraph G, a retraction of H to G is a homomorphism r:H→G such that r(x)=x for all vertices x in G. We call G a retract of H. While deciding the existence of a retraction to a fixed graph G is NP-complete in general, necessary and sufficient conditions have been provided for certain classes of graphs in terms of holes, see for example Hell and Rival.For any integer k?2 we describe a collection of graphs that generate the variety AR_k of graphs G with the property that G is a retract of H whenever G is a subgraph of H and no hole in G of size at most k is filled by a vertex of H. We also prove that AR_k⊂NUF_k+1, where NUF_k+1 is the variety of graphs that admit a near unanimity function of arity k+1.