Ring Closure To Form Metal Chelates in 3D Fragment-Based de Novo Design.

We describe a method for the design of multicyclic compounds from three-dimensional (3D) molecular fragments. The 3D building blocks are assembled in a controlled fashion, and closable chains of such fragments are identified. Next, the ring-closing conformations of such formally closable chains are identified, and the 3D model of a cyclic or multicyclic molecule is built. Embedding this method in an evolutionary algorithm results in a de novo design tool capable of altering the number and nature of cycles in species such as transition metal compounds with multidentate ligands in terms of, for example, ligand denticity, type and length of bridges, identity of bridgehead terms, and substitution pattern. An application of the method to the design of multidentate nitrogen-based ligands for Fe(II) spin-crossover (SCO) compounds is presented. The best candidates display multidentate skeletons new to the field of Fe(II) SCO yet resembling ligands deployed in other fields of chemistry, demonstrating the capability of the approach to explore structural variation and to suggest unexpected and realistic molecules, including structures with cycles not found in the building blocks.

Regional variations in the concentrations of ketone bodies in cirrhosis and hepatic encephalopathy: a study in patients with TIPSS.

BACKGROUND: Little is known about the metabolism of acetoacetate and ß-hydroxybutyrate in patients with cirrhosis and encephalopathy. AIMS: We investigated the fate of ketone bodies in these conditions. MATERIALS AND METHODS: We studied 18 cirrhotic patients with encephalopathy and 17 cirrhotics without. At the time of insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) or at the time of portographical assessment of the shunt's patency, we collected blood from the internal jugular, the right atrium, the inferior vena cava, the hepatic, the portal, the splenic veins and the radial artery. We used nuclear magnetic resonance spectroscopy to measure the concentrations of acetoacetate and ß-hydroxybutyrate. RESULTS: There was no difference in the total ketone body concentrations between the two groups. The mitochondrial redox potential was significantly higher in the encephalopathics (142/54=2.63 vs 52/83=0.62) (P<0.01). ß-hydroxybutyrate was significantly lower in the portal vein of encephalopathics (52 ± 4 vs 28 ± 3) (P<0.02) and in the splenic vein (48 ± 6 vs 32 ± 5) (P<0.04). Acetoacetate was significantly higher in encephalopathics in the internal jugular vein (134 ± 12 vs 92 ± 16) (P<0.03), the right atrium (112 ± 18 vs 68 ± 11) (P<0.03), the hepatic vein (162 ± 25 vs 115 ± 19) (P<0.05), the portal vein (133 ± 20 vs 81 ± 14) (P<0.02) and the splenic vein (167 ± 24 vs 122 ± 21) (P<0.04). All measurements are expressed in µmols/L. CONCLUSIONS: There are significant variations in the regional concentrations of the ketone bodies in encephalopathy.