The first total synthesis of chaetocin (
1), a potent histone methyltransferase inhibitor, is described in detail. Key reactions were radical bromination for α-oxidation of the diketopiperazine ring, ...and reductive radical coupling for construction of the dimeric core structure. Stereoselective construction of the disulfide bridges was achieved via substitution reaction with H
2S. The total synthesis of
1 was accomplished in nine steps starting from known
d-amino acid derivatives. Total synthesis of non-natural
ent-chaetocin (
ent-
1) was also achieved via the established synthetic route, starting from
l-amino acid derivatives.
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Epipolythiodiketopiperazine (ETP) alkaloids are structurally characterized by the presence of diketopiperazine rings having sensitive (poly)sulfide bridges, and most of them are classified as fungal ...secondary metabolites. Various biological activities have been reported for members of this family, including cytotoxic, antibacterial, antimicrobial, antiviral, antitumor, antiallergic, and antimalarial activities. Notably, some of the molecules were reported to show specific inhibitory activities against certain critical enzymes. Since the supply of these compounds from natural sources is quite limited, efficient chemical syntheses of ETP alkaloids would be useful for biological studies. However, total syntheses of ETP alkaloids remain a formidable challenge in current synthetic organic chemistry because of their structural complexity. In this review article, we present an overview of synthetic approaches to the ETP alkaloids during the past 50 years, and discuss significant milestones. We also summarize the biological activities of these compounds, focusing on the molecular mechanisms.
Chaetocin (1), a structurally complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetomium minutum, is a potent inhibitor of protein lysine methyltransferase G9a, which plays important ...roles in many biological processes. Here we present our synthetic investigations to identify a simple prototype G9a inhibitor structure based on structure–activity relationship (SAR) studies on chaetocin derivatives. The simple derivative PS-ETP-1 (14) was found to be a potent G9a inhibitor with greatly reduced cytotoxicity.
The unnatural enantiomer of chaetocin (
ent-chaetocin) was more potent than chaetocin, and was found to induce apoptosis through the caspase-8/caspase-3 activation pathway.
Chaetocin, a natural ...product isolated from
Chaetomium species fungi, was reported to have various biological activities, including antitumor and antifungal activities. Recently, we reported the first total synthesis of chaetocin and its derivatives. Here, we examined the cell-death-inducing activity of these compounds in human leukemia HL-60 cells. The unnatural enantiomer of chaetocin (
ent-chaetocin) was more potent than chaetocin, and was found to induce apoptosis through the caspase-8/caspase-3 activation pathway.
The first total synthesis of (+)-chaetocin has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction of diketopiperazine 10 and Co(I)-mediated ...reductive dimerization reaction of 12 as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogues without the sulfur functionality are inactive.
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are ...potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600 000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼3 log-orders to yield compound 35 (K i = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
The increasing power consumption in servers is a problem in data centers. One approach to address this is to optimize physical resource allocation for virtualized functions. For this approach, power ...consumption needs to be estimated, and many papers have proposed models to estimate server power consumption. However, applying such estimation techniques to data center servers presents an operational challenge. Specifically, it is difficult to reduce the cost of model building and data collection while maintaining estimation accuracy. To address this problem, we propose a management system with a modeling function and a data selection function. The modeling function builds accurate models in accordance with application requirements, and the data selection function selects data related to server power consumption and then instructs data collection to each processing server. Our main effort in this paper was to address the monitoring function issue to reduce server power consumption during data collection. We analyze the relationship between server performance data and server power consumption and reduce the type of data. Experimental results showed that our selected data are sufficient to construct a server power modeling. Furthermore, by limiting the amount of data collected, we were able to reduce server power consumption by about 3 W and monitoring overhead by about 30%.
Model predictive sensor scheduling Eriko Iwasa; Uchida, K.
2008 International Conference on Control, Automation and Systems,
2008-Oct.
Conference Proceeding
The sensor scheduling is to select a sensor (or a group of sensors) from multiple sensors at each time step so as to perform optimally a task based on the sensed data. In this paper, we pose a model ...predictive type deterministic/stochastic sensor scheduling problem for discrete-time linear Gaussian time-varying systems, and develop an approach to solve these problems based on the dynamic programming recursion. We show first that, in a special case of deterministic scheduling where the Riccati recursion of error covariance satisfies a specific structural condition, the online optimization using the dynamic programming is reduced to a static optimization, so that the model predictive sensor scheduling can be easily implemented online. Next, we discuss the stochastic scheduling problem, and show an alternative condition of optimization reduction, which lead to a stochastic sensor scheduling easily implemented online. Finally, we propose two practical sensor schedulings for deterministic and stochastic case, and discuss an example to illustrate the two sensor schedulings.
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