Stereochemical Assignment of the 36-Membered Macrolide Ring Portion of Poecillastrin C.

Absolute configuration at 12 stereocenters in the 36-membered macrocyclic ring portion of poecillastrin C (1) was disclosed by chemical degradation and NMR analyses of 1, chemical synthesis, and molecular modeling techniques.

Catalytic Enantioselective Synthesis of C1 - and C2 -Symmetric Spirobiindanones through Counterion-Directed Enolate C-Acylation.

A catalytic enantioselective route to C1 - and C2 -symmetric 2,2'-spirobiindanones has been realized through an intramolecular enolate C-acylation. This reaction employs a chiral ammonium counterion to direct the acylation of an in situ generated ketone enolate with a pentafluorophenyl ester. This reaction constitutes the first example of a direct catalytic enantioselective C-acylation of a ketone and provides an efficient and highly enantioselective route to axially chiral spirobiindanediones. These products can be diastereoselectively derivatized, offering access to a range of functionalized spirocyclic architectures.

Evaluation of the Impact of Excipients and an Albendazole Salt on Albendazole Concentrations in Upper Small Intestine Using an In Vitro Biorelevant Gastrointestinal Transfer (BioGIT) System.

An in vitro biorelevant gastrointestinal transfer (BioGIT) system was assessed for its ability to mimic recently reported albendazole concentrations in human upper small intestine after administration of free base suspensions to fasted adults in absence and in presence of supersaturation promoting excipients (hydroxypropylmethylcellulose and lipid self-emulsifying vehicles). The in vitro method was also used to evaluate the likely impact of using the sulfate salt on albendazole concentrations in upper small intestine. In addition, BioGIT data were compared with equilibrium solubility data of the salt and the free base in human aspirates and biorelevant media. The BioGIT system adequately simulated the average albendazole gastrointestinal transfer process and concentrations in upper small intestine after administration of the free base suspensions to fasted adults. However, the degree of supersaturation observed in the duodenal compartment was greater than in vivo. Albendazole sulfate resulted in minimal increase of albendazole concentrations in the duodenal compartment of the BioGIT, despite improved equilibrium solubility observed in human aspirates and biorelevant media, indicating that the use of a salt is unlikely to lead to any significant oral absorption advantage for albendazole.

The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor.

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

A library-site asthma education program for inner-city communities.

Asthma education programs are reportedly effective for children and adolescents. Urban and minority children continue to have poor asthma outcomes and limited access to asthma education programs. The purpose of this study was to determine whether a library-based asthma education program, the Columbus Ohio Partnership for Inner-City Asthma Education (COPICAE), offered to urban and minority children (with their parents) could improve asthma-related outcomes and reduce billing claims for asthma-related hospital visits. A prospective/observational study was conducted to evaluate asthma-related outcomes of 87 children who completed 6 hours of asthma education using telephone follow-up at 12 and 24 months with a scored Living With Asthma Survey (LWAS). Hospital billing claims for asthma as the primary diagnosis were compared over a 24-month period for 64 children who completed 6 hours of asthma education with an age and zip code match control. Two separate focus groups with Spanish-speaking and English-speaking parents who completed 6 hours of asthma education with their children obtained parental perspectives about the asthma education classes. LWAS follow-up data were obtained on 67% of the participants at year 1 and 43% at year 2. Compared to pre-intervention mean scores, there were decreases in scores to all LWAS items. Parents reported improvements in compliance with asthma medication use and overall control of their child's asthma. Parents also found the information from the asthma education classes to be "beneficial." Total asthma-related billing claims for children who completed 6 hours of asthma education decreased 63.2%, while those for age and zip code matched controls increased 0.7%. Inner-city and minority children (with their parents) who attended 6 hours of asthma education offered in a public library showed improvements in asthma-related outcomes over a 24-month period and decreased billing claims for asthma-related hospital visits. Parents found 6 hours of asthma education to be beneficial in gaining basic knowledge about asthma and improving their child's illness control and self-esteem in living with asthma.