The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.

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In the present study calcium hydroxyapatites enriched at 0.08 wt% in Mn 2+ ions (Mn-HA) and their unsubstituted forms (HA) were synthesized using the same standard wet chemical route. Mn-HA and HA were both calcined at 800°C to give Mn-HAc and HAc, respectively or sintered at 1250°C, to give Mn-HAs and HAs, respectively. The influence of the heat treatment on physicochemical properties of Mn-HA was investigated using powder X-ray diffraction (PXRD), scanning, and transmission electron microscopy (SEM and TEM), and solid-state nuclear magnetic resonance (ssNMR). Mn-HAc and Mn-HAs were compared to each other and to HAc and HAs, respectively. Assignment of the proton ssNMR peaks from high-temperature-treated apatites has been revised. It was found that Mn-HAc and HAc were nanocrystalline, while Mn-HAs and HAs comprised micrometer sized, partially fused particles (SEM and TEM). PXRD and ssNMR demonstrated that the incorporation of Mn 2+ into the crystal lattice of hydroxyapatite significantly facilitates its dehydroxylation and decomposition to oxyhydroxyapatite during calcination at 800°C, and induces its transformation to tetracalcium phosphate (TTCP) and alpha-tricalcium phosphate (a-TCP) at 1250°C. Contamination by CaO has also been detected. The 1 H? 31 P NMR cross-polarization experiments have indicated that the Mn 2+ ions preferentially occupied the Ca(I) position in the crystallographic unit cell of Mn-HAc. In Mn-HAs, the Mn 2+ ions were evenly distributed between the Ca(I) and Ca (II) positions.

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