Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub ؉1 , has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub ؉1 expression should be deleterious. Here we show that Ub ؉1 is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub ؉1 in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.
A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamide. Results and discussion Methods For our study, we elected to use five of the most common amide coupling reagents or reagent combinations: (1-cyano-2ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), 12 N,N′-diisopropylcarbo-† Electronic supplementary information (ESI) available: Experimental procedures, analytical data, charts of conversion vs. time for all substrates in all solvents and for all coupling agents. See
SummaryPd-catalysed C–C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, these solvents are incompatible with the drive towards more sustainable chemical synthesis. Herein, we describe the scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira cross-coupling and Cacchi-type annulations.
The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data.
A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic processes
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.