- Synthetic modeling of the structure and function of the rare-earth dependent methanol dehydrogenase cofactor
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Historically, rare-earth ions have been considered irrelevant to biology. Recently, the active sites of certain methanol dehydrogenase (MDH) enzymes have been shown to contain a redox-inactive, rare-earth (RE) cation coordinated by the redox-active pyrroloquinoline quinone (PQQ) cofactor. Importantly, it was demonstrated that rare earths were essential for the growth of certain methylotrophs that incorporated the XoxF-MDH. In this chapter, we summarize the optimized synthesis of a previously published rare-earth complex that serves as a model of the active site of this RE-containing MDH enzyme. The structure and reactivity of the metalated complex, [La(LQQ)(NO3)3] are also discussed. [La(LQQ)(NO3)3] catalytically oxidizes the test alcohol substrate, p-methylbenzyl alcohol, 4MeBnOH, to p-methylbenzaldehyde, 4MePhCHO, in the presence of a base (2,6-lutidine) and a terminal oxidant (ferrocenium hexafluorophosphate) with ~ 17 turnovers. By studying this synthetic model, we have developed a body of evidence about both the reactivity and the mechanism of dehydrogenation of alcohols as a molecular analogue to a native, rare-earth dependent enzyme.
- Knasin, Alison L.,Schelter, Eric J.
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- Antitumor agents. 5. Synthesis, structure - activity relationships, and biological evaluation of dimethyl-5H-pyridophenoxazin-5-ones, tetrahydro-5H-benzopyridophenoxazin-5-ones, and 5H-benzopyridophenoxazin-5-ones with potent antiproliferative activity
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New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5H-benzopyrido[2,3-j]phenoxazin-5-ones (7-9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10-12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1-6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7-9 were scarcely active, whereas the corresponding benzo derivatives 10-12 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors π-π stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 10-12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase.
- Bolognese, Adele,Correale, Gaetano,Manfra, Michele,Lavecchia, Antonio,Novellino, Ettore,Pepe, Stefano
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p. 5110 - 5118
(2007/10/03)
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