Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel

We obtained unanticipated synthetic byproducts from alkylation of the δ[superscript 1] nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C[subscript 6]H[subscript 5](CH[subscript 2])[subscript 8]– group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents.National Institutes of Health (U.S.) (Grant GM60594)National Institutes of Health (U.S.) (Grant GM68762)National Institutes of Health (U.S.) (Grant CA112967

New phosphoranes with five- and seven-membered rings: influence of the nature of the substituents on hydrogen bonding

Several pentacoordinated phosphoranes with a primary amino substituent have been synthesized by oxidative addition reactions on a cyclic phosphite. X-ray structures of three of these, i.e. (C6H11NH)P(2,2'-O-C6H4-C6H4-O)(1,2-O2C6Cl4) (6), (C6H11NH)P(9,10-O2C14H8)(1,2-O2C6H4) (7) and (MeNH)P(2,2'-O-C6H4-C6H4-O) (1,2-O2C6H4) (8) have been determined. While 6 does not show hydrogen bonding interactions involving the NH proton, compound 7 is a weak dimer with hydrogen bonding interactions between the NH proton and the apical oxygen of the catecholate ring. By contrast in 3, although hydrogen bonding again involves the NH proton and apical oxygen of the five-membered catecholate ring, a polymeric chain structure is formed. (C) 2000 Elsevier Science Ltd All rights reserved

What happens to the vitamin E in a vitamin-stabilised HXLPE?

Today many of the second-generation highly cross-linked polyethylenes (HXLPE) use vitamin E (chemical name: α-tocopherol) as antioxidant to further enhance the longevity of the implant. There are two main technologies how to add the vitamin E to the polyethylene: by infusion or by blending. Depending on the manufacturing and sterilisation process and the chosen level of cross-linking, the vitamin E will thus be subjected to different amounts of high energy irradiation

Synthesis Of Pentacoordinate Silicon Complexes From Sio2

THE potential role of inorganic and organometallic silicon compounds in the development of new chemical reagents, polymers, glasses and ceramics 1 is limited at present by the paucity of simple silicon-containing starting materials. Whereas industrial carbon-based chemistry can draw on the diversity of compounds produced from crude oil, coal or other natural sources, silicon chemistry 2 relies almost exclusively on the carbothermal reduction of SiO2 to silicon. This is then transformed into feedstock chemicals by reaction with HCl, or by routes such as the 'direct process' for making methylchlorosilanes 2, in which silicon is reacted with methyl chloride at 200-350-degrees-C over a copper/tin catalyst. Organosilicon compounds are in demand in fields ranging from organic synthesis to ceramics to the electronics industry. New synthetic routes to these materials are therefore highly desirable, especially if they rely on low-cost SiO2 and on processing methods that avoid the energy-intensive and equipment-intensive carbothermal reduction step which currently precedes almost all silicon chemistry. Here we describe a direct process in which SiO2 is reacted with ethylene glycol and an alkali base to produce highly reactive, pentacoordinate silicates which provide access to a wide variety of new silicon compounds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62810/1/353642a0.pd