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Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.

The alkylsulfatase AtsK from Pseudomonas putida S-313 belongs to the widespread and versatile non-heme iron(II) α-ketoglutarate-dependent dioxygenase superfamily and catalyzes the oxygenolytic cleavage of a variety of different alkyl sulfate esters to the corresponding aldehyde and sulfate. The enzyme is only expressed under sulfur starvation conditions, providing a selective advantage for bacterial growth in soils and rhizosphere. Here we describe the crystal structure of AtsK in the apo form and in three complexes:  with the cosubstrate α-ketoglutarate, with α-ketoglutarate and iron, and finally with α-ketoglutarate, iron, and an alkyl sulfate ester used as substrate in catalytic studies. The overall fold of the enzyme is closely related to that of the taurine/α-ketoglutarate dioxygenase TauD and is similar to the fold observed for other members of the enzyme superfamily. From comparison of these structures with the crystal structure of AtsK and its complexes, we propose a general mechanism for the catalytic cycle of the α-ketoglutarate-dependent dioxygenase superfamily.

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Isolated cells of Saccharomyces cerevisiae were mated by micromanipulation and the reproductive capacity of the resulting zygotes was determined. The mating frequency was dependent on the age of the parents: conjugations between young cells and cells which had completed more than two thirds of their life-span were very rare events. The life-span of a zygote was very similar to the life-span of its shorter-lived parent. If one of the parent cells had budded several times prior to fusion, the life-span of the zygote was reduced correspondingly, i.e. there was no 'rescue by hybridization.' In four crosses the distribution of buds on both of the parent cells was recorded. In three of these four crosses the buds were evenly distributed, and in one the alpha-parent had three times as many buds as the a-parent.

The first enantioselective syntheses of the Ipecacuanha alkaloid emetine (1) and the Alangium alkaloid tubulosine (2) is described employing a domino Knoevenagel/hetero-Diels-Alder reaction and an enantioselective catalytic transfer hydrogenation of imines as key steps. Thus, hydrogenation of the imine 15 with the catalyst (R,R)-16 gives the tetrahydroisoquinoline 14 with 95 % ee which was transformed into the aldehyde (1S)-7. The three-component domino reaction of (1S)-7 with 6 and 8 led to 19, which in a second domino process was treated with K(2)CO(3) in methanol followed by a hydrogenation to give the benzoquinolizidine 4 together with the diastereomers 22 and 23 in a overall yield of 66 %. Further transformation of 4 with the amines 3 and 5 yielded enantiopure emetine (1) and tubulosine (2), respectively. In addition, starting from 19 the novel benzoquinolizidine alkaloid 34 was synthesised; this compound resembles the vallesiachotamine alkaloid dihydroantirhin 31, which has not been isolated so far but probably must also exist in nature.

Keywords: Cadmium / Manganese / N ligands / ZincWe have focused on the synthesis of monomeric, functionalized starting materials containing manganese(II), zinc(II), and cadmium(II) by taking advantage of the sterically demanding and chelating property of the substituted vinamidine ligand 2-[(2,6-diisopropylphenyl)amino]-4-[(2,6-diisopropylphenyl)imino]pent-2-ene (NacNacH). Metal iodine derivatives containing vinamidines as the bulky ligand can be regarded as interesting precursors for preparing complexes with low-valent metal centers by reduction as

The reaction of the b-diketoiminate lithium complex (dipp)NacNacLi´OEt 2 ((dipp)NacNac = 2-((2,6-diisopropylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-pent-2-enyl) with iPrMgCl and MgI 2 yield the corresponding (dipp)NacNacMgiPr´OEt 2 (1) and (dipp)NacNacMgI´OEt 2 (2). The reaction of 2 with NaBH 4 in diethylether gives (dipp)NacNacMg(l-H) 3 BH´OEt 2 (3). The core element of compounds 1±3 is a six-membered ring formed by N(1)±C(1)±C(2)±C(3)±N(2) and magnesium. The structures of 1 and 2 show the b-diketoiminate backbone in a boat-conformation with the tetrahedrally coordinated metal center at the prow and the opposing carbon atom at the stern. The magnesium atom in 3 is octahedrally coordinated and out of the b-diketoiminate plane. Synthese und Struktur von b-Diketiminato Komplexen des MagnesiumsInhaltsu È bersicht. Die Reaktion des b-Diketiminato-LithiumKomplexes (dipp)NacNacLi´OEt 2 ((dipp)NacNac = 2-((2,6-Diisopropylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-pent-2-enyl) mit iPrMgCl bzw. mit MgI 2 fu È hrt zur Bildung des entsprechenden (dipp)NacNacMgiPr´OEt 2 (1) und (dipp)NacNacMgI´OEt 2 (2). Durch Umsetzung von 2 mit NaBH 4 in Diethylether wird das (dipp)NacNacMg-(l-H) 3 BH´OEt 2 (3) erhalten. Das zentrale Strukturelement der Verbindungen 1±3 ist ein sechsgliedriger Ring bestehend aus N(1)±C(1)±C(2)±C(3)±N(2) und Magnesium. Die Strukturen von 1 und 2 stellen die b-Diketiminatoverbindungen in einer Bootkonformation dar, mit dem tetraedrisch koordinierten Metallatom auf der einen und dem gegenu È berliegenden Kohlenstoffatom auf der anderen Seite. Das Magnesiumatom in 3 ist oktaedrisch koordiniert und liegt auûerhalb der Ebene, die durch den b-DiketiminatoLiganden gebildet wird.