No abstract

The ubiquitin-proteasome system (UPS) [1] has been related to many different diseases including multiple myeloma, where the core protein of the UPS, the 20S proteasome (CP), has been successfully targeted by the blockbuster drug Velcade (Bortezomib).[2] The repeated emphasis on the vast therapeutic potential of CP inhibitors in different diseases and the primary resistance and ineffectiveness of current market drugs against some types of solid tumors have proven the need for not only second-generation CP inhibitors but also for the discovery of inhibitors with a new mechanism of action.The eukaryotic CP is composed of four stacked heptameric rings, each comprising a-and b-type subunits in an a 1À7 b 1À7 b 1À7 a 1À7 stoichiometry.[3] Embedded in these sandwiched b-subunits are three different active sites with distinct cleavage preferences known as caspase(C)-, trypsin(T)-, and chymotrypsin(CT)-like activities. The active-site nucleophile Thr1O g is located in subunits b1, b2, and b5 (C-, T-and CTlike activities), respectively; however, it is the composition of active and surrounding subunits of the substrate-binding pockets which give rise to the substrate-cleaving preferences. [4] To date, all CP inhibitors are known to have either a peptidelike structure, which forms an antiparallel b sheet with the substrate-binding channel of the active sites, and/or reactive head groups which covalently bind to the threonine residue Thr1O g .[5] These characteristics have previously been related to excessive reactivity, lack of specificity, and/or instability. Furthermore, there are currently few CP inhibitors that do not simultaneously inactivate all three active sites of the CP. In fact, studies have shown that inactivation of the b5 active site alone is enough to attain therapeutic effects. [6,7] We performed screening experiments using specific b5 fluorogenic tetrapeptide substrates in order to search for nonpeptide-based inhibitors with reversible binding to the CT-like active site. These experiments were performed using a library of inhibitors from Bayer CropScience AG. One of the hits identified was an N-hydroxyurea(HU)-based compound (1, Table 1). Interestingly, this inhibitor is a known 5-lipoxygenase inhibitor (U.S. Pat. No. 5,714,633) closely related to ZyfloCR (Zileuton; Figure S1 in the Supporting Information) a internationally prescribed drug for the treatment of asthma.[8] Surprisingly, 1 showed unique binding to the CT-like active site of the yeast CP with an IC 50 of 230 mm (K i = 23 mm ; Table 1) with no inhibition observed for the Cand T-like activities even at an inhibitor concentration of 200 mm ( Figure S2 in the Supporting Information).Additionally this inhibitor has no structural similarities with any other known inhibitor of the CP. Moreover, it (1-Ad)O Me (S) [b] 57 AE 2.5 5.75 AE 0.25 10(1-Ad)O Me (R) [c] 0.34 AE 0.04 0.034 AE 0.004[a] No inhibition against T-or C-like activity was observed at concentrations as high as 200 mm ( Figure S2).[b] C* in S configuration.[c] C* in R configuration.[

Pestalone (1) is a prominent marine natural product first isolated by M. Cueto et al. in 2001 from a co-fermentation of a marine fungus with a marine bacterium. For more than 10 years, 1 had been considered as a promising new antibiotic compound, the reported MIC against methicillin-resistant Staphylococcus aureus (MRSA) being 37 ng/mL. After overcoming the limited availability of 1 by total synthesis (N. Slavov et al., 2010) we performed new biological tests, which did not confirm the expected degree of antibiotic activity. The observed activity of pestalone against different MRSA strains was 3-10 μg/mL, as determined independently in two laboratories. A number of synthetic derivatives of 1 including pestalachloride A and other isoindolinones (formed from 1 by reaction with amines) did not exhibit higher activities as compared to 1 against MRSA and a series of plant pathogens.

No abstract

An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.