Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochemical profiling of a series of compounds, including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compound collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn(2+) -dependent HDACs. Potent inhibition was observed with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate class I and class IIb HDAC inhibitors.

Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen. Nevertheless, it has been speculated that using macrocyclic compounds to target HDAC enzymes might hold an advantage over the use of traditional hydroxamic‐acid‐containing inhibitors, which rely on chelation to the conserved active‐site zinc ion. Here we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and on structure–activity relationship studies inspired by these molecules, as well as on efforts aimed at fully synthetic macrocyclic HDAC inhibitors.

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A generic computer model for systematic investigations of container ship designs is described in this paper. The primary statistical data on container ships used for the model development are also presented. The model can be used to calculate exhaust gas emissions from container ships, including emissions of carbon dioxide (CO2). A calculation procedure to estimate the newly designated Energy Efficiency Design Index (EEDI), which is under development at the International Maritime Organization (IMO), is included in the model. Different ship design parameters have been varied to see the influence of these parameters on the EEDI. It is found possible to reduce EEDI by roughly 20 % without reducing ship speed, but only by changing some of the design parameters, such as reducing the sea margin by using a derated main engine, increasing the length of the ship by 5 %, and reducing steel weight by 3 % via steel weight optimization.

The back cover picture shows coordination of a novel silanediol histone deacetylase (HDAC) inhibitor to a Zn 2+ atom in the active site of a human HDAC enzyme. The equilibrium between keto and hydrated forms of a structurally related trifluoromethyl-ketone-containing inhibitor is also shown. The compounds are part of an array of inhibitors, which was synthesized and profiled for their potencies against recombinant human HDACs 1À11. For further details, see the Full Paper by Christian A. Olsen et al. on p. 614 ff.