For none of the actives any PI-103 371935-74-9 reference to COX inhibition was found, and only for compound 9 substructure matches were retrieved with regard to bioactivities other than COX inhibition. It is therefore reasonable to conclude that COX inhibition by compounds 5 and 9 represents a novel finding resulting from our study. We did not perform additional analytical investigations of compound integrity and purity other than those provided by the compound supplier. Therefore, we cannot exclude that the activities measured in the assays might be partially owed to decomposition or oxidation products. Analog compound design and testing will be mandatory. Histone deacetylases regulate the acetylation status of histones and other intracellular substrates. Four classes of HDACs have been identified, three of which are NAD + independent HDACs. The recently discovered class III HDACs are sirtuins. Mammalian sirtuins are homologs of the yeast silent information regulator 2, and are characterized by a unique NAD + -dependent enzymatic activity. Classical HDACs have long been known for their involvement in cancer, including leukemias. Aberrant HDAC activity is commonly observed in leukemia cells, leading to skewed gene expression, increased proliferation, and resistance to apoptosis. HDAC inhibitors, some of which have been available for decades, show antileukemic activity in vitro and in animal models, and thus underwent clinical evaluations, mostly for acute myelogenous leukemia and myelodysplastic syndromes. Overall, these agents are very well tolerated, which makes them particularly suited for treating elderly patients or patients with relevant co-morbidities. However, although the most recent inhibitors, 
such as vorinostat and romidepsin, appear to be more active than traditional valproic acid, HDAC NVP-BEZ235 915019-65-7 inhibitors alone will rarely induce disease remissions, their benefit being mostly limited to hematological improvements. Thus, strategies to increase their efficacy are warranted. Recently, sirtuins, particularly SIRT1, have also been proposed to play a role in leukemogenesis. SIRT1 was found to be overexpressed in AML and in B-cell chronic lymphocytic leukemia, and downregulated during neutrophil differentiation of acute promyelocytic leukemia cells. It was reported that SIRT1 antagonizes PML-induced cellular senescense. Moreover, increased SIRT1 levels were detected in chemoresistant leukemia cells and in imatinib-resistant chronic myelogenous leukemia cells. The mechanisms invoked to explain SIRT1��s oncogenic activity are mostly related to its role in cell defenses and survival in response to stress. SIRT1 directly deacetylates, and consequently inactivates, p53. Moreover, SIRT1 prevents apoptosis in response to damage or stress by interfering with the activity of the FOXO family of transcription factors, of Bax, Rb, and of E2F1. Sirtuins are virtually unaffected by all HDAC inhibitors currently available. However, numerous small-molecule sirtuin inhibitors have been described, several of which show anticancer activity in preclinical models. Moreover, nicotinamide phosphoribosyltransferase inhibitors, such as FK866, by lowering intracellular NAD + concentrations, deprive sirtuins of their substrate and thus reduce their activity. Indeed, in many instances, pharmacological Nampt inhibition has been shown to recreate the biological consequences of sirtuin obstruction or genetic deletion. In this study, we evaluated sirtuin inhibitors and FK866, either alone or in combination with HDAC inhibitors.