New fixed point theorem under R-contractions

In this manuscript we introduce the notions of R-function and R-contractions, and we show an ad hoc fixed point theorem. We prove that this new kind of contractions properly includes the family of all Meir-Keeler contractions and other well-known classes of contractions that have been given very recently (for instance, those using simulation functions and manageable functions). As a consequence, our approach turns out to be appropriate to unify the treatment of different kinds of contractive nonlinear operators.This article was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah. The second author, therefore, acknowledges with thanks DSR for technical and financial support. The authors are grateful to three anonymous referees for their useful suggestions and comments. AF Roldán López de Hierro is grateful to the Department of Quantitative Methods for Economics and Business of the University of Granada. The same author has been partially supported by Junta de Andalucía by project FQM-268 of the Andalusian CICYE

Investigations into the mechanisms of pyridine ring cleavage in vismodegibs

Vismodegib (Erivedge, GDC-0449) is a first-in-class, orally administered small-molecule Hedgehog pathway inhibitor that is approved for the treatment of advanced basal cell carcinoma. Previously, we reported results from preclinical and clinical radiolabeled mass balance studies in which we determined that metabolism is the main route of vismodegib elimination. The metabolites of vismodegib are primarily the result of oxidation followed by glucuronidation. The focus of the current work is to probe the mechanisms of formation of three pyridine ring-cleaved metabolites of vismodegib, mainly M9, M13, and M18, using in vitro, ex vivo liver perfusion and in vivo rat studies. The use of stable-labeled (13C2,15N)vismodegib on the pyridine ring exhibited that the loss of carbon observed in both M9 and M13 was from the C-6 position of pyridine. Interestingly, the source of the nitrogen atom in the amide of M9 was from the pyridine. Evidence for the formation of aldehyde intermediates was observed using trapping agents as well as 18O-water. Finally, we conclude that cytochrome P450 is involved in the formation of M9, M13, and M18 and that M3 (the major mono-oxidative metabolite) is not the precursor for the formation of these cleaved products; rather, M18 is the primary cleaved metabolite. Copyright 2014 by The American Society for Pharmacology and Experimental Therapeutic

Enzymatic aerobic ring rearrangement of optically active furylcarbinols

Biogenic furans are currently discussed as highly attractive alternative feedstock in a post-fossil society; thus, also the creation of sustainable furan valorization pathways appears of great importance. Here an artificial Achmatowicz monooxygenase activity for the aerobic ring expansion of furans is achieved by the combination of commercial glucose oxidase as oxygen-activating biocatalyst and wild-type chloroperoxidase as oxygen-transfer mediator, providing a biological ready-to-use solution for this truly synthetic furan rearrangement. In concert with enzymatic transformations for the enantioselective preparation of optically active furylcarbinols, purely biocatalytic reaction cascades for the stereocontrolled construction of complex pyranones are obtained, exhibiting high functional group tolerance even to oxidation-sensitive moieties