We report structure-activity relationships for organometallic RuII complexes of the type [(eta6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY=ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY=bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene=p-cymene, XY=amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY=en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

The effect of high pressure on the crystal structures of -, -and -glycine has been investigated. A new polymorph, δ-glycine, is obtained from  glycine. δ-Glycine is monoclinic, P2 1 /a, a = 11.156(4), b = 5.8644(11), c = 5.3417(17) Å,  = 125.83(4)° at 1.9 GPa. The transition, which occurs between 0 and 0.8 GPa, proceeds from a single crystal of -glycine to a single crystal of δ-glycine, resulting in an equal number of NH…O hydrogen bonds, but an increase in the number and strength of CH…O hydrogen bonds, which act to close-up of 'holes' which are formed within the layers of -glycine in the centers of R-type hydrogen bonded motifs. Trigonal -glycine begins to undergo a transition to another high-pressure phase, -glycine, at 1.9 GPa, but the transformation is destructive; it is essentially complete at 4.3 GPa. The structure is monoclinic Pn, a = 4.8887(10), b = 5.7541(11), c = 5.4419(11) Å,  = 116.682(10)° at 4.3 GPa. The structure consists of layers similar those observed in -glycine with inter-layer separations of 2.38 and 3.38 Å and CH…O interactions formed between the layers. Monoclinic -glycine is known to be stable to 23 GPa, and we have obtained a single crystal structure of this polymorph at 6.2 GPa. Super-short NH…O hydrogen bonds are not formed up to 6.2 GPa, and they only shorten significantly if they are formed parallel to CH…O hydrogen bonds which strengthen, or vectors across holes which close-up, under pressure.

The synthesis and X-ray structure (as the tetrahydrate) of the platinum(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 3 are described and its photochemistry and photobiology are compared with those of the cis isomer cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 4. Complexes 4 and 3 are potential precursors of the anticancer drug cisplatin and its inactive trans isomer transplatin, respectively. The trans complex 3 is octahedral, contains almost linear azide ligands, and adopts a layer structure with extensive intermolecular hydrogen bonding. The intense azide-to-platinum(IV) charge-transfer band of complex 3 (285 nm; epsilon=19 500 M(-1) cm(-1)) is more intense and bathochromically shifted relative to that of the cis isomer 4. In contrast to transplatin, complex 3 rapidly formed a platinum(II) bis(5'-guanosine monophosphate) (5'-GMP) adduct when irradiated with UVA light, and did not react in the dark. Complexes 3 and 4 were non-toxic to human skin cells (keratinocytes) in the dark, but were as cytotoxic as cisplatin on irradiation for a short time (50 min). Damage to the DNA of these cells was detected by using the "comet" assay. Both trans- and cis-diammine platinum(IV) diazide complexes therefore have potential as photochemotherapeutic agents.

Chlamydia trachomatis ͉ enzyme structure ͉ fatty acid binding ͉ enzyme mechanism

Although CCD instruments are now widely used in single-crystal diffraction, they have not been employed so extensively in crystallographic studies at high pressure. This paper describes some practical experience in the application of one CCD instrument, the Bruker±Nonius SMART APEX (a ®xed-1 instrument). Centring a sample in a pressure cell is complicated by the restrictions on viewing the sample imposed by the body of the cell. The data collection strategy is de®ned by the requirements that (i) the incident beam must illuminate the sample and (ii) no more than 80% of the detector should be shaded by the body of the pressure cell. High-pressure diffraction images are contaminated by powder lines from the gasket and backing-disk materials, which form part of the pressure cell, and very intense spots from the diamond anvils. Procedures for the selection of spots for indexing are described. Integration routines attempt to harvest intensity data from regions of the detector that are shaded by the body of the pressure cell, and a procedure for generating dynamic masks is described. Shading also reduces the volume of reciprocal space that can be sampled, although this can be increased by performing data collections at more than one pressure-cell setting. Corrections for absorption are carried out in a two-stage procedure comprising an analytical correction for absorption by the cell, followed by a second multi-scan correction. Data sets collected at high pressure often contain some signi®cant outliers; these can be identi®ed during merging using a robust resistant weighting scheme, as described by Blessing [J.

SummaryThe protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP + and the inhibitor determined at 2.2 Å resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the b6-a6 loop and a6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis.

Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by 6 -arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [(( 6 -biphenyl)RuCl(en)) 2 -(CH2)6] 2؉ (3, en ‫؍‬ ethylenediamine) was elucidated by studies of the half unit [( 6 -biphenyl)RuCl(Et-en)] ؉ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated R* RuR * N and S* RuR * N diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t1/2 Ϸ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the R* RuR * N configurations are more stable than S* RuR * N (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to S* RuR * N diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.

We thank Professor G. R. Desiraju for suggesting crystallization of pyridine-d¬5¬, and STFC for provision of neutron beam-time and a studentship for SC. RB gratefully acknowledges the support of the DFG FOR 618. [ † ] We dedicate this paper to Dr Frank Allen on the occasion of his retirement as Executive Director of the Cambridge Crystallographic Data Centre. Supporting information:Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Crystallographic information files can be obtained from the Cambridge Crystallographic Data Centre, quoting deposition numbers CCDC 695956 -695959. A summary table of crystal data is also given in the Supporting Information.