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The negative regulation of p53, a major human tumor suppressor, by Mdm2 and Mdmx is crucial for the survival of a cell, whereas its aberrant function is a common feature of cancer.  Both Mdm proteins act through the spatial occlusion of the p53 transactivation (TA) domain and by the ubiquitination of p53, resulting in its degradation.  Two p53 homologues, p63 and p73, have been described in humans.  Unlike p53, these proteins regulate developmental processes rather than genome stability.  Both p63 and p73 contain TA domains homologous to that of p53, but relatively little is known about their regulation by Mdm2 or Mdmx.  Here, we present a detailed characterization of the interaction of Mdm2 and Mdmx with the TA domains of p63 and p73. Earlier reports of Mdm2 and Mdmx interactions with p73 are substantiated by the detailed quantitative characterization reported in this study. Most importantly, earlier contradictions concerning the presumed interaction of the Mdm proteins with p63 are convincingly resolved and for the first time, the affinities of these interactions are determined.  Finally, the contribution of these findings to our understanding of the physiological role of these interactions is discussed.

Kinetics of the thermal fragmentation of four N-substituted derivatives of 0-ethyl phosphoramidic acids, (EtO-P(O)(NRR')(OH), were examined. When N contained either of the sterically demanding mesityl or 1-adamantyl groups, the reaction followed first-order kinetics, both in the absence and presence of an alcohol trapping reagent. In the former case, the product was a pyrophosphate (RR'N(EtO)(O)P-O-P(O)(OEt)OH). In the latter case, phosphorus was trapped as a dialkyl phosphate. Both reactions are therefore indicated to follow an elimination-addition mechanism, with ethyl metaphosphate as transient intermediate. The pyrophosphate is derived from reaction of the metaphosphate with unreacted phosphoramidic acid. With less bulky substituents (N-phenyl or NJV-diethyl), mixed firstand second-order kinetics were followed in the absence of a trapping agent; some bimolecular interaction of the substrate to form the pyrophosphate product is indicated by the second-order kinetics. Product analyses and quantitative measurements were made with 31P NMR spectroscopy. From all phosphoramidic acids, the intermediate metaphosphate was effectively trapped by reaction with the OH group on the surface of solid silica gel. The presence of covalently bonded phosphate on the surface was shown by 31P and 29Si CP/MAS NMR spectroscopy. Abstract: Jankowski, S.; Quin, L. D.; Flubacher, D. Phosphorus Sulfur Silicon 1993, 77, 236.) (2) Quin, L. D.; Pete, B.; Szewczyk, J.; Hughes, A. N. Tetrahedron

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4-Benzoyl-1-(4-methyl-imidazol-5-yl)-carbonylthiosemicarbazide (1) was synthesized, and its antibacterial and type IIA topoisomerase (DNA gyrase and topoisomerase IV) activity evaluated. (1) was found to have high therapeutic potential against opportunistic Gram-positive bacteria, and inhibitory activity against topoisomerase IV (IC(50)=90 μM) but not against DNA gyrase. An increase in activity against topoisomerase IV (IC(50)=14 μM) was observed when the imidazole moiety of (1) was replaced with the indole group in 4-benzoyl-1-(indol-2-yl)-carbonylthiosemicarbazide (2). However, (2) showed only weak antibacterial activity. Although the results of the bacterial type IIA topoisomerases inhibition study did not parallel antibacterial activities, our observations strongly imply that a 4-benzoylthiosemicarbazide scaffold can be developed into an efficient Gram-positive antibacterial targeting topoisomerase IV. The difference in activity against type IIA topoisomerases between (1) and (2) was further investigated by docking studies, which suggested that these compounds target the ATP binding pocket.

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