Targeted Synthesis of Complex Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96_MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2′-pyrrolo[2,3-c]pyrrole]-2,4′-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects.     

The use of microwave irradiation for the easy synthesis of graphene-supported transition metal nanoparticles in ionic liquids

Stable ruthenium or rhodium metal nanoparticles were supported on chemically derived graphene (CDG) surfaces with small and uniform particle sizes (Ru 2.2 ± 0.4 nm and Rh 2.8 ± 0.5 nm) by decomposition of their metal carbonyl precursors by rapid microwave irradiation in a suspension of CDG in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate. The graphene-supported hybrid nanoparticles were shown to be active and could be re-used at least 10 times as catalysts for the hydrogenation of cyclohexene and benzene under organic-solvent-free conditions with constant activities up to 1570 mol cyclohexane × (mol metal)⁻¹ × h⁻¹ at 4 bar and 75 °C.     

Mental Fitness.

The author explores Andie Knutson's plea for a more appropriate term to describe the positive aspects of mental health (see record 1964-01167-001) and suggest the term mental fitness. She provides the definition of fitness and explains that this concept of mental fitness carries much of the connotation we are groping for. It forms an excellent counterpart for the late President Kennedy's program for physical fitness. At the same time, it avoids the unfortunate connotation of illness, and consequent restriction to medical care. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Historical contamination of Yukon Lake sediments by PCBs and organochlorine pesticides: influence of local sources and watershed characteristics

PCBs and other persistent organochlorine (OC) pesticides were analyzed in sediment cores collected from six lakes in Yukon Territory and one in northern British Columbia, Canada, with the objective of establishing sources and historical trends of these contaminants. DDT was found to be the most prominent OC in the sediment profiles of most of the lakes. Maximum sigmaDDT levels (3.47-2680 ng g(-1) dw) were observed in sediment slices dated to the 1950s from lakes near populated areas. In contrast, in more remote lakes (Hanson, Kusawa and Lindeman), the maximum sigmaDDT concentrations were observed in the sediments dated to the 1970s. Highest sigmaPCB and sigmaDDT concentrations were measured in sediments from Watson Lake, near a suspected PCB waste disposal site and in a region where DDT was heavily applied in the 1950s and 1960s. Elevated sigmaPCB concentrations [16.1-93.6 ng g(-1) dry weight (dw)] were also observed in sediments from lakes situated near populated areas, relative to Kusawa and Lindeman (11.1 and 12.7 ng g(-1) dw, respectively). Recent sigmaPCB fluxes ranged from 621 ng m(-2) y(-1) in Kusawa Lake to 16400 ng m(-2) y(-1) in Little Atlin Lake. The extremely high sedimentation rate (2050 g m(-2) y(-1)) in glacial fed Lindeman Lake gave rise to elevated fluxes of sigmaPCB (2410 ng m(-2) y(-1)) and other OCs, despite much lower concentrations in the sediment. Levels of hexachlorocyclohexanes (sigmaHCH), chlordane-related compounds (sigmaCHL), and chlorobenzenes (sigmaCBz) were in the low ng g(-1) (dw) range in all lake sediments, similar to concentrations previously reported for Arctic lakes in Canada, indicating that their major source was long range atmospheric transport. Contamination of the lakes with PCBs and DDT near populated areas of the Yukon Territory appears to be a result of regional activities rather than long range transport and deposition. The results also point to glacial runoff as a significant source of OCs to small, high elevation lakes (Lindeman), but not to larger lakes within the Yukon River drainage basin that are also affected by glacial sources (Kusawa, Laberge).     

Short time creep behaviour of Invar steel

During processing of so‐called true flat shadow/masks made of Invar steel for large size TV screens the mask is stretched onto a solid frame. Mask and frame are submitted to a final heat treatment (blackening treatment) in order to enhance the emissivity of the material. Elevated temperatures and pretension makes the mask material prone to plastic straining, resulting in disutility of the unit for the application. From a technological point of view, the material behaviour under these conditions has been defined as short time creep behaviour. The mechanisms causing creep in this special case are not fully understood. Focus of the present work was the examination of the effect of cube twins on the short time creep behaviour of the investigated Invar steel by texture analysis using EBSD technology. This investigation was conducted under four different material conditions covering a whole set of production steps during shadowmask processing. Detailed information about the change of the volume fractions and the orientation of characteristic texture components, most of all the cube twins, could be gained. The observations revealed that during the creep test two types of cube twins make an orientation change, thus plastic deformation takes place, causing relaxation of the material. The observation of cube twin rotation during the creep test is partly confirmed by the simulation of the respective Taylor factors.     

Review of Revitalizng retirement: Reshaping your identity, relationships, and purpose.

Reviews the book, Revitalizng retirement: Reshaping your identity, relationships, and purpose by Nancy K. Schlossberg (2009). Therapists, counsellors, and life coaches working with older middle-age adults will find this handbook to happiness in retirement a useful working tool. The author introduces the book by stating that some content resembles notes she resurrected from a freshman undergraduate lecture on personal development; accordingly, both the format and the issues discussed in this book generalise to life span motivational needs, but the intended focus is on the transition to retirement. As a result, this book would make a useful tool for a support group or workshop on psychosocial transitions in postemployment life, with some limitations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)