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J. Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 3903 Bioinorganic Chemistry a personal perspective * C. David Garner Chemistry Department The University of Manchester Oxford Road Manchester UK M13 9PL Bioinorganic Chemistry is an interdisciplinary field of science which draws on the strengths of the disciplines of Inorganic Chemistry and Biological Sciences and requires the application of advanced physical and theoretical methodologies. The articles in this special volume illustrate the state of knowledge in five topics each of considerable current interest and development oxomolybdenum and oxotungsten enzymes; small molecule activation by metalloproteins; biomineralisation; mixed-valence metal clusters in biology; and metals in medicine. This special volume of Dalton Transactions is comprised of the presentations given at the Dalton Discussion No.2. This meeting follows the successful inaugural Dalton Discussion meeting on the theme of ‘Clusters’ held at Southampton University 3rd– 5th January 1996.1 The format for these meetings involves a series of keynote lectures presented by leading scientists of international standing plus a larger number of other speakers invited to deliver a short lecture based on an article submitted prior to the meeting. All presenters are required to produce a contribution to Dalton Transactions which is refereed in the manner and to the standards normally required by the journal. These articles are made available to all participants prior to the meeting. The subsequent publication serves as a permanent record of the meeting and a valuable reference source on the particular topics covered.The nature of Dalton Discussions is still evolving but it is already clear that they will become important events in the scientific calendar of the Royal Society of Chemistry and will lead to influential issues of Dalton Transactions. Bioinorganic Chemistry is experiencing rapid and sustainable development with many fundamental academic challenges and strategically important problems being addressed. The field derives considerable stimulus from the synergy arising from the interdisciplinary approach to the search for new knowledge which draws on the expertise available from the Chemical and Biological Sciences and uses the power of advanced physical and theoretical methodologies. The resolution available from structural methods particularly state-of-the-art protein crystallography and NMR techniques allows the structure and function of biological systems to be clearly elucidated in chemical terms.Also a detailed understanding of a biological system and the identification of its unique features require complementary information from relevant chemical systems. Furthermore an important practical consideration is that the spectroscopic techniques used to probe metal centres in biological systems need to be calibrated by parallel investigations of well defined and relevant chemical analogues. Dalton Discussion No. 2 was organised along the lines of its predecessor. Five themes were chosen from the many possible within Bioinorganic Chemistry and for each two keynote speakers were selected on the basis of the significant contributions they and their research group have made to advance the state of knowledge of the particular topic.The themes and keynote lecturers were Oxomolybdenum and oxotungsten enzymes – D. C. Rees and E. I. Stiefel Small molecule activation by metalloproteins – A. M. Valentine and L. Que Jr. * Based on the presentations given at Dalton Discussion No. 2 2nd–5th September 1997 University of East Anglia UK. Biomineralisation – G. A. Ozin and S. Mann Mixed-valence clusters in biology – D. Gatteschi and G. Blondin Metals in medicine – J. Reedijk and B. Lippert Eight of these keynote lectures are reported as Perspectives one as a Paper and the other as a Communication; the shorter presentations are reported as 18 Papers and one Communication. An especially pleasing aspect of the meeting was the relatively large number of presentations given by younger scientists.The meeting received further and significant impetus from some 48 poster contributions which gave an excellent focus for extensive informal discussions. Each of the sessions was chaired by one (or in one case two) authorities in the field who ensured that a lively and focused discussion followed each of the presentations with contributions from the 135 participants drawn from 14 different countries. The key elements of the discussions are reported herein in the format adopted for the first Dalton Discussion meeting.1 The task of providing a detailed overview reporting all of the views and comments expressed during the meeting as a supplement to this excellent collection of articles is not feasible without significantly delaying the publication time of this issue.Therefore what follows is a personal perspective on each of the five themes concentrating on important issues which emerged during the meeting. Oxomolybdenum and Oxotungsten Enzymes D. C. Rees presented an excellent review of his important protein crystallographic contributions 2 which together with other such structural studies have transformed the status of this topic. In particular the results of this research have conclusively defined the nature of the special pterin [2-amino-4(1H)- pteridinone] (molybdopterin Fig. 1) bound to Mo and W in these enzymes and unambiguously determined the metal:pterin ratio. The chemistry of the molybdenum-containing enzymes was placed in an admirably clear Perspective3 by E.I. Stiefel on the basis of the protein crystallographic studies accomplished for representatives of the oxomolybdoenzymes and the nitrogenases. For the former group of enzymes the information now available indicates that the ‘molybdenum cofactor’ should now Fig. 1 Structure of molybdopterin 2 N HN NH HN O H2N O SH SH OPO3 2– 3904 J. Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 be viewed as a generic term for a family of prosthetic groups. The variations include (i) one or two molecules of the pterin bound to the Mo; (ii) the presence or absence of a nucleotide appended to the phosphate of the pterin; (iii) variation in the co-ordination chemistry at the metal. An important aspect of these presentations and the subsequent discussion was the requirement to integrate the protein crystallographic studies with spectroscopic investigations of these systems.This is essential. Firstly because of the limitations in the precision of the measurements especially in respect of the identification of the non-protein and non-pterin ligands of the Mo and W centres. Secondly the current nature of X-ray crystallography is such that ambiguities over the oxidation level of the metal centre during the experiment arise and the precision of the structural data is insufficient to resolve questions regarding oxidation levels of the pyrazine pyran and dithiolene rings of the metal–pterin assembly. Thirdly there is a fundamental need to fully characterise the chemical state and the homogeneity of the enzyme studied by protein crystallography. These problems are highlighted by the three different structures of native dimethyl sulfoxide reductase each with the protein and pterin structures invariant but with significantly different Mo centres.Also sulfite oxidase which has been characterised spectroscopically as the prototypical cis-MoVIO2 centre but protein crystallography has identified a mono-oxo centre! The discussion concentrated upon several chemical aspects of the protein crystallographic results. The special ligand for the metals in these enzymes has the same conformation in all structures so far determined as would be expected if there is a common genetically controlled pathway for the biosynthesis of molybdopterin. A nucleotide is appended to the molybdopterin in some but not all of these enzymes; whilst this serves to anchor the centre within the protein it is interesting to speculate whether the nucleotide has another role.The molybdopterin supplies the dithiolene (ene-dithiolate) group which coordinates to the Mo or W and the question arises as to whether the redox properties of the metal centre are coupled in any way to those of the pyrazine ring. One intriguing possibility is that the pyran ring could open leading to unsaturation of the pyrazine ring which would be conjugated to the dithiolene ring.3 The ‘non-innocent’ nature of the dithiolene ligands is well established (see Fig. 2) and the challenge still exists for chemists to understand the electronic structure of dithiolenes especially as the protein crystallographic and resonance-Raman studies of the oxomolybdoenzymes have identified different types of dithiolene groups.Of course the redox chemistry of sulfur (and selenium) is rich and the coupling of the metal-based and chalcogenide-based redox chemistry has been elegantly developed by Stiefel3 and this behaviour is likely to be a feature of the reactivity of the metal centres in the oxomolybdenum and oxotungsten enzymes. These keynote lectures were complemented by four other presentations. One was concerned with the synthesis of [MoIVO(dithiolene)2]2– complexes 4 and another with the mechanism of O-atom transfer between such systems and their cis- MoVIO2 counterparts.5 The nature of the intermediate(s) formed in the O-atom transfer reactions of chemical systems and how these might relate to the natural systems was discussed. The advances made in the theoretical treatment of Fig. 2 Redox activity of an ene-dithiolate (dithiolene) ligand 3 S– S– S S Dithiolate S S Dithione Dithiete or –2 e– 2 e– transition-metal centres in proteins is now starting to have a major impact in Bioinorganic Chemistry and this has been used to good effect for some molybdenum centres including xanthine oxidase.6 The need to integrate the results of these calculations with experimental data e.g.EPR parameters was stressed during discussion. Major advances have been achieved in defining the structure of molybdate- and tungstate-binding proteins.7 The anions are embedded in the protein matrix by a set of hydrogen-bonding interactions. The structure of the Azotobacter vinelandii periplasmic molybdate-binding protein is very similar to that of the sulfate-binding protein of Salmonella typhimurium.This raises the question of the basis of the anion selectivity. The discussion considered MoO4 22 WO4 22 SO4 22 and PO4 32 and how the ‘venus-fly trap’ binding proteins might discriminate between them; is it on the basis of size the electrostatic potential on the surface of the tetrahedron the pKb of the anion or a combination of these factors? Also the mechanism for release of the anions is unclear. Small Molecule Activation by Metalloproteins An especially important aspect of Bioinorganic Chemistry is the catalyses which are accomplished by metalloenzymes particularly as many of these transformations are difficult to duplicate outside of the natural system. Metalloenzymes can activate chemical bonds which are inert and control the subsequent transformation to achieve an elegant specificity.These capabilities represent intriguing aspects of the structure and function of the active site of the soluble methane monooxygenase (sMMO) from Methylococcus capsulatus (Bath).8 This enzyme is comprised of three proteins with the catalytic site of the hydroxylase involving a non-heme diiron centre. The carboxylate-bridged diiron centres in sMMO activate dioxygen and methane to accomplish under ambient conditions a reaction which can only be duplicated industrially at high temperature and pressure. Thanks to the achievements of several research groups the sequence of events in the catalytic cycle for sMMO is (Fig. 3) well defined. The discussion following the accomplished keynote lecture of A. M. Valentine,8 concentrated upon the chemistry of the intermediates in the catalytic cycle of sMMO.This considered the spectroscopic information available for the transient species with reference to the protein crystallographic results of Rosenzweig Lippard et al. which have provided a clear view of the molecular architecture of this protein. The enzyme possesses a hydrophobic pocket adjacent to the catalytic site for substrate Fig. 3 Catalytic cycle for sMMO from M. capsulatus (Bath) showing observed intermediates 8 NADH NAD+ + H+ FAD Fe Fe S S Reductase FeIII HO FeIII CH4 CH3OH + H2O Resting Hydroxylase 2H+ O2 FeIII FeIII CH4 CH4 Q CH4 FeII FeII CH4 FeIII FeIII O O Hperoxo Protein B J. Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 3905 binding prior to reaction with O2 at the diiron centre. How O2 binds to the diiron centre and the nature of the peroxo intermediate which converts spontaneously to a bright yellow intermediate (Q) remain to be established.Intermediate Q is generally considered to react with CH4 to form CH3OH and although some spectroscopic characterisation of Q has been achieved the nature of this centre has not been defined and thus the essence of the catalytic action remains elusive. Some important distinctions between sMMO and the Cu-dependent membrane-bound methane monooxygenase were elaborated during the discussion. Oxidation of NH3 is accomplished reasonably readily by the Cu enzyme but not by sMMO and this could be because the former enzyme may involve a different type of pocket for initial substrate binding. The presence of Cu suppresses the biosynthesis of sMMO and there is clearly gene regulation of this process; however this does not appear to involve stimulation of the biosynthesis by the presence of CH4.The awareness of the presence of carboxylate-bridged nonheme diiron centres as a common structural motif for several metalloproteins that bind and/or activate dioxygen (Fig. 4) has stimulated important developments in related co-ordination chemistry.9 Not only have the spectroscopic studies of the chemical systems been vital for the interpretation of spectra recorded for the natural systems but also this chemistry has been influential in considerations of the structure and properties of the reactive centres of the metalloproteins. This last point is especially true for the compounds obtained by reacting diiron centres with O2 and Que et al. have made important progress by identifying the Fe2O2 ‘diamond core’ in chemical systems.This is a well characterised type of centre as Mn2O2 and Cu2O2 (of course the analogous Fe2S2 moiety is the building block of Fe]S clusters) and the proposition that M2(m-O)2 moieties are common to metalloproteins which activate or produce O2 has considerable attractions. Rapid freeze–quench 57Fe Mössbauer and Fe K-edge EXAFS studies of sMMO have shown that the inter- Fig. 4 Non-heme diiron active sites of several important metalloproteins 9 His241 FeII O O FeII O O O Glu115 His118 O Asp84 Glu238 FeII O FeII O O O His246 O O Glu144 His147 O Glu209 OH2 Glu243 O Glu114 His232 FeII O O FeII O O O Glu143 His146 O Glu105 Glu229 O O Glu196 O O Glu204 FeIII O FeIII OH O O His246 O O O Glu144 His147 Glu114 O O Glu209 O Glu243 H H H O FeII O FeII O O His77 His54 His73 His101 His25 O O H Glu58 O O Asp106 FeIII O FeIII O O His77 His54 His73 His101 His25 Glu58 O O Asp106 fatty acid desaturase hemerythrin Diiron(II) (proposed) methane monooxygenase hydroxylase component His241 FeIII O O FeIII O O O Glu115 His118 O O Glu238 Asp84 O O Glu204 H OH2 H2O His FeIII Glu O FeIII Glu O O Glu His O O Glu ribonucleotide reductase R2 protein Diiron(III) mediate Q is a diiron(IV) species with an unusually short Fe ? ? ?Fe separation of 2.5 Å and one short (1.8 Å) Fe]O bond per Fe in addition to four Fe]O/N bonds that average 2.04 Å.An asymmetric Fe2(m-O)2 diamond core would be consistent with these data. How this centre hydroxylates CH4 is still a matter of speculation. The knowledge gained from metalloenzymes which activate small molecules has greatly stimulated co-ordination chemistry.Novel developments in the synthesis of iron(III)–metal(II) complexes as structural models of the active centre of purple acid phosphatases have been accomplished.10 A CuIIN5 centre which can be oxidised electrochemically to give CuII adjacent to an aryl radical cation is of relevance to galactose oxidase; the results obtained suggest that p-stacking interactions do not contribute to stabilisation of the radical cation. 11 An extensive series of electrochemical studies of the oxidation and protonation of a bridging amide ligand at a dinuclear metal–sulfur site has been accomplished.12 These results clearly demonstrate that an amide ligand which is believed to be an intermediate in biological nitrogen fixation can be protonated to NH3 at a dinuclear sulfur co-ordinated metal site.In the discussion it was pointed out that the role of the sulfur could be important in such reactions e.g. for H1 binding. Biomineralisation Biomineralisation centres on the idea that an organic matrix controls the nucleation growth and form of inorganic materials and it is this process that creates hierarchical composite structures with unusual chemical and physical properties. The meeting was treated to two impressive keynote lectures by G. A. Ozin 13 and S. Mann.14 These showed the beautiful morphology which can be obtained for inorganic materials formed in the presence of a suitable organic template and the advances made in mimicking these processes. The challenges to understand and fully replicate the biological processes are considerable but the returns will be immensely valuable if it proves possible to reproduce the elegant connection of form to function achieved by Nature.Ozin described the mineralisation of silicate and phosphate in liquid-crystal phases to create morphologies with ‘natural’ forms.13 Many illustrations were given of the formation of silicates to produce fascinating morphologies (see Fig. 5) using simple well-defined procedures in which the aggregation occurs in surfactant micelles. Much of the subsequent discussion centred on the chemistry of the control of the deposition of the Si]O aggregate within the surfactant micelle especially the pH at the surface of the Si]O aggregate and how to measure this. Fig. 5 A scanning electron microscopy image of a high curvature mesoporous synthetic silicate 13 3906 J.Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 The use of electric fields kinetic isotope effects the presence of particular anions and variation in the nature of the siliconcontaining species were all discussed as further possible ways of controlling the morphology. Mann emphasized that the interplay between the intrinsic molecular forces of inorganic precipitation and the extrinsic field arising from longer-range cellular activity and organisation is pivotal in explaining the extraordinary complex form of biominerals (see Fig. 6).14 The reaction space can control the shape of the mineral e.g. curved rods of SiO2 can be produced in a curved vesicle and a network of vesicles can give a honeycombed array. However it is important to note that the reaction space may not be static and there is a general need to study the dynamics of biomineralisation processes.The role of trace elements in the control of morphology may be important but from studies of chemical systems these effects relate to the symmetry of the unit cell and the growth of a particular face (or faces); Nature has developed the means of overruling the morphology of the unit cell. Biomimetic inorganic materials chemistry aims to exploit the principles of biomineralisation to control crystal morphology and synthesise novel materials. Whilst this is typically demonstrated for compounds of the s- and p-block elements the principles are quite general. The meeting heard of the influences of amphiphiles on the crystallisation of CuSO4? 5H2O15 and the control over magnetite crystal morphology exerted by the oxalate template.The stabilisation of an intermediate new synthetic iron oxyhydroxy oxalate phase has enabled the action of oxalate in directing this crystal growth to be clearly discerned.16 Ferritins are vital FeIII storage proteins and a major challenge is to understand the mechanism of the oxidative uptake of FeII via the dinuclear centres which have been identified in subunits of the protein shell. New spectroscopic studies have identified a transient blue species.17 The chemical nature of this species is intriguing and site-directed mutagenesis experiments indicate that it is not an iron–tyrosinate complex; could it be an FeIII 2– peroxo moiety? The important inter-relationships between Cu and Fe metabolism continue to attract much attention but the chemistry of these connections remains difficult to define.One potentially important aspect of this inter-relationship is the influence of CuII on the rate of aerobic oxidative uptake of FeII by horse spleen apoferritin.18 Since commercial ferritin contains copper this must be removed in experimental work so that a controlled addition of CuII can be achieved. It is not clear where the CuII binds; one possibility is the formation of dinuclear Fe ? ? ? Cu centres in the transport channels. Humic acids are ubiquitous in soils and serve to bind metals with an extraordinary capacity and tenacity. This behaviour is important not only to agriculture but also for soil remediation and water quality. The meeting heard of progress made in Fig. 6 Hollow spherical shell of calcium carbonate (aragonite) formed by synthesising a cellular mineralised film on polymer microspheres (scale bar = 200 nm) 14 understanding the chemistry of these systems; there is no evidence for the formation of metal clusters or aggregates within the organic matrix.19 The question of pH control of metal binding was raised and whether metals migrate from one site to another.Mixed-valence Metal Clusters in Biology Mixed-valence transition-metal clusters are vital for the function of many metalloenzymes and redox active metalloproteins. These allow multi-electron catalyses to be controlled and facilitate electron transfer over long distances since electrons can (generally) move freely within the cluster. The challenges of (amongst other things) defining the electronic and magnetic structures of mixed-valence clusters; the coupling of electronic and vibrational motions; the degree of electronic delocalisation; and spin-dependent electronic delocalisation are considerable.An armoury of sophisticated methodologies (calibrated by studies on suitable structurally characterised chemical systems) has been successfully employed to analyse and determine the electronic and magnetic structures of these centres. Mixed-valence chemistry is particularly rich for manganese with the oxygen evolving complex (OEC) of Photosystem II being the most enigmatic case. The theoretical basis for describing mixed-valence in metal clusters derives from the classical treatments of chemical and mineralogical systems. D. Gatteshi authoritatively showed that the magnetic coupling between mixed-valence centres provides a useful tool for investigating the structure of the arrangement; the coupling can be assessed both by direct magnetisation measurements and from indirect spectroscopic measurements.This point of view was clearly justified by a review of the magnetic interactions between pairs of Mn ions concentrating on the spin-dependent electron transfer in MnIII–MnIV pairs which originates the ferromagnetic double exchange and then extending the perspective to larger clusters comprising 4–12 Mn centres.20 The larger arrays of Mn centres are being investigated as possible candidates for singlemolecule magnets (Fig. 7) especially because these systems display thermally assisted quantum tunnelling. The prospect of the controlled incorporation of other metals into the Mn12 structure to achieve a variation in magnetic properties was considered during the discussion.Inorganic systems which involve four Mn centres in close proximity have potential relevance to the OEC of Photosystem II; a wide range of such systems has attracted attention as the structure of the natural system is not yet established. Although Fig. 7 Representation of the spin structure of the core of [Mn12O12(O2CCH3)16(H2O)4] 20 J. Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 3907 crystals of Photosystem II have been obtained the resolution of the diffraction patterns (>4 Å) is not sufficient to provide information at atomic resolution and so the nature of the Mn centre is being elucidated spectroscopically principally from EPR and X-ray absorption studies. G. Blondin presented the results of an elegant study whereby g-irradiation of a dimethylformamide solution of [MnIV 4O6(bipy)6]41 (bipy = 2,29- bipyridine) (Fig.8) at 77 K has produced the first example of a mixed-valence tetranuclear centre containing MnIII and MnIV centres which exhibits an S = ��� ground state. The analysis of the EPR signal of [Mn4O6(bipy)6]31 has contributed to an improved understanding of that observed for the S2 state of the OEC.21 As was pointed out during the discussion this EPR-active species should be structurally characterised by Mn K-edge Xray absorption spectroscopy in situ linked to the isolation and the determination of the crystal structure. The meeting also learned of the progress made in calibrating the Mn K-edge EXAFS of the OEC by parallel studies on chemical systems notably one containing alkali- and alkaline-earth-metal cations in a crown ether moiety adjacent to a dinuclear manganese centre.22 Copper is used widely in biology because of its facile CuII– CuI redox chemistry which becomes intriguing when two or more Cu centres are in close proximity.The novel binuclear CuA centres of cytochrome c oxidase and N2O reductase with equivalent Cu atoms in the mixed-valence CuII–CuI oxidation state has set challenges to understand the electronic structure of these centres including the pathway for exchange and to synthesise chemical systems with similar properties. Fully delocalised class III mixed-valence dicopper co-ordination complexes containing a CuIICuI core are comparatively rare. However an octaazacryptate ligand will encapsulate such a centre; UV/VIS and MCD measurements linked to theoretical calculations have successfully determined the electronic structure of this centre.23 A new trinuclear CuII assembly has been synthesised and structurally characterised the spectroscopic properties of which may have relevance to those of the trinuclear copper active sites of ascorbate oxidase and laccase.One possible extension of this chemistry is the interaction of the complex with DNA for which it shows a high affinity.24 Metals in Medicine The use of inorganic-based systems as pharmaceuticals and agents which aid medical diagnosis is rapidly developing as are the techniques to probe the metabolism and mode of action of these metal complexes. These studies together with complementary chemical developments are leading to an improved understanding of the biological behaviour of the complexes and the design and development of new variants.These develop- Fig. 8 Structure of [MnIV 4O6(bipy)6]4121 ments are important for metal anti-cancer complexes in order to circumvent cell resistance and to produce agents with an improved efficacy and minimal undesirable side effects. The majority of studies have concentrated on PtII compounds following the initial discovery and widespread clinical use of ‘cisplatin’ cis-[PtCl2(NH3)2] and its second and third generation successors. Although PdII compounds with their similar chemistry might also appear attractive the rates of ligand exchange for PtII complexes (min/h) are compatible with the time-scale of drug administration and delivery whilst those of the PdII systems (103–105 times faster) are not.Platinum anti-cancer drugs are believed to exert their therapeutic action through interactions with DNA the ultimate target being the N7 of guanine. We do not know how the Pt species reaches the DNA especially as PtII complexes are known to react rapidly with sulfur-donor ligands such as cysteine and methionine which are present within a cell. Thus as brought out in the discussion metallothionines could scavenge platinum anti-cancer drugs. J. Reedijk clearly showed that the nucleopeptide Met-d(TpG) (59-O-methioninate-N-ylcarbonylthymidine 29-deoxyguanosine monophosphate) (see Fig. 9) containing a methionine moiety covalently linked to a TpG dinucleotide reacts with platinum complexes. The initial binding gives PtII�S co-ordination for [Pt(dien)Cl]Cl (dien = diethylenetriamine) this is subsequently substituted by the N7 atom of guanine; in the case of the cisplatin analogue [Pt(en)Cl2] (en = ethane-1,2-diamine) the formation of a stable S,Nchelate occurs.25 The salt [Pt([15N]dien)Cl]Cl has been used extensively as a model for the first step in binding of platinum anti-tumour compounds to DNA although the compound itself is inactive.New [1H,15N] NMR studies of the reactions of [Pt([15N]dien)- Cl]Cl have provided valuable spectroscopic correlations and have raised questions about the role of hydrolysis in the mechanism of binding of this complex to DNA bases.26 Our present understanding of basic principles of metal ion–nucleobase/nucleic acid interactions is clearly incomplete. Fig. 9 Structure of the nucleopeptide Met-d(TpG); arrows indicate possible platinum binding sites 25 Fig.10 Mispair between N7 platinated N1 deprotonated guanine and neutral guanine as found in cis-[Pt(NH3)2(egua)2]?Hegua (Hegua = 9-ethylguanine) 27 3908 J. Chem. Soc. Dalton Trans. 1997 Pages 3903–3908 Despite a rapid increase in structural information derived from X-ray data and NMR work and thermodynamic data (stability constants) of model systems many essential features of the effects of metal ions on nucleic acids or their constituents are still poorly understood. Metal ions stabilise duplex triplex and quadruplex DNA structures by relieving the repulsion between the negatively charged polynucleotide strands. The binding of metals to DNA profoundly changes the pKa and chemistry of the nucleotide bases and therefore the base pair interactions.B. Lippert 27 provided an impressive and comprehensive survey of this field demonstrating from an extensive range of structurally characterised chemical systems (e.g. Fig. 10) how the binding of PtII and other heavy later transitionmetal centres can lead to modifications to normal Watson– Crick or Hoogsteen base-pairing and produce mis-matches and/or other novel assemblies. This valuable information should form the basis of further studies to examine the reactivity of these systems especially the ability of the metal to migrate from one Lewis base to another. Thus as noted in discussion an understanding of the dynamics of metal binding to sites on DNA is a vital aspect of understanding the role of metal-based anti-cancer agents. A manganese cationic porphyrin covalently linked to the 59 end of an antisense oligonucleotide has been shown to mediate sequence-specific oxidative lesions on an mRNA target when activated by KHSO5;28 this action may involve an MnV]] O centre.The clinical use of the anthracycline antibiotic doxorubicin in cancer chemotherapy although extensive is limited by its severe negative side effects; complexation by metal ions is one of the many strategies used to reduce the toxicity of this drug. The interaction of SnCl4 with doxorubicin has been followed spectroscopically and two sites for SnIV binding have been identified.29 The nature of the interactions between this drug and metal ions normally present in humans still needs to be established. Some stable metal chelates of polyfunctional macrocyclic ligands have considerable value for radiopharmaceutical and MRI applications.A new 18-membered hexaaza macrocyclic ligand with four pendant methylenephosphonates has been synthesised and characterised and its properties and those of its LaIII complex investigated; the ligand encapsulates the metal ion by providing 10 donor atoms.30 Acknowledgements Janet Dean Graham McCann and all the team involved with Dalton Transactions are congratulated for the rapid production of excellent printed versions of the contributed papers prior to the meeting. Dr. John Gibson Ms. Nicola Durkan and Ms. Jane Carlton are thanked for their very efficient administration of the whole meeting. We are grateful for the provision of the excellent conference facilities of the John Innes Centre. The Organising Committee conf Dr.A. K. Powell (Chair) Dr. R. N. F. Thorneley Professors C. D. Garner G. R. Moore P. J. Sadler and A. J. Thomson each of whom contributed much to the planning of the meeting in addition to chairing a session and leading discussions. Special mention is made of the effective leadership and commitment of Annie Powell which ensured a successful outcome of the whole enterprise. Drs. Yan Zang and Raymond Y. N. Ho (University of Minnesota) are thanked for providing the cover artwork. References 1 J. Evans J. Chem. Soc. Dalton Trans. 1996 555. 2 D. C. Rees Y. Hu C. Kisker and H. Schindlin J. Chem. Soc. Dalton Trans. 1997 3909 and refs. therein. 3 E. I. Stiefel J. Chem. Soc. Dalton Trans. 1997 3915 and refs. therein. 4 E. S. Davies R. L. Beddoes D. Collison A. Dinsmore A. Docrat J.A. Joule C. R. Wilson and C. D. Garner J. Chem. Soc. Dalton Trans. 1997 3985. 5 C. Lorber M. R. Plutino L. I. Elding and E. Norlander J. Chem. Soc. Dalton Trans. 1997 3997. 6 M. R. Bray and R. J. Deeth J. Chem. Soc. Dalton Trans. 1997 4005. 7 D. M. Lawson C. E. Williams D. J. White A. P. Choay L. A. Mitchenall and R. N. Pau J. Chem. Soc. Dalton Trans. 1997 3981 and refs. therein. 8 A. M. Valentine and S. J. Lippard J. Chem. Soc. Dalton Trans. 1997 3925 and refs. therein. 9 L. Que jun. J. Chem. Soc. Dalton Trans. 1997 3933 and refs. therein. 10 M. Ghiladi C. J. McKenzie A. Meier A. K. Powell J. Ulstrup and S. Wocadlo J. Chem. Soc. Dalton Trans. 1997 4011. 11 M. A. Halcrow E. J. L. McInnes F. E. Mabbs I. J. Scowen M. McPartlin H. R. Powell and J. E. Davies J. Chem. Soc. Dalton Trans.1997 4025. 12 F. Y. Pétillon P. Schollhammer and J. Talarmin J. Chem. Soc. Dalton Trans. 1997 4019. 13 N. Coombs D. Khushalani S. Oliver G. A. Ozin G. C. Shen I. Sokolov and H. Yang J. Chem. Soc. Dalton Trans. 1997 3941 and refs. therein. 14 S. Mann J. Chem. Soc. Dalton Trans. 1997 3953 and refs. therein. 15 R. Tang C. Jiang and Z. Tai J. Chem. Soc. Dalton Trans. 1997 4037. 16 M. Moliner D. J. Price P. T. Wood and A. K. Powell J. Chem. Soc. Dalton Trans. 1997 4061. 17 Z. Zhao A. Treffry M. A. Quail J. R. Guest and P. M. Harrison J. Chem. Soc. Dalton Trans. 1997 3977. 18 J. McKnight N. White and G. R. Moore J. Chem. Soc. Dalton Trans. 1997 4043. 19 G. Davies A. Fataftah A. Cherkasskiy E. A. Ghabbour A. Radwan S. A. Jansen S. Kolla M. D. Paciolla L. T. Sein jun. W. Buermann M. Balasubramanian J.Budnick and B. Xing J. Chem. Soc. Dalton Trans. 1997 4047. 20 A. Caneschi D. Gatteschi and R. Sessoli J. Chem. Soc. Dalton Trans. 1997 3963 and refs. therein. 21 G. Blondin R. Davydov C. Philouze M.-F. Charlot S. Styring B. Åkermark J.-J. Girerd and A. Boussac J. Chem. Soc. Dalton Trans. 1997 4069. 22 S. Turconi C. P. Horwitz Y. Ciringh S. T. Weintraub J. T. Warden J. H. A. Nugent and M. C. W. Evans J. Chem. Soc. Dalton Trans. 1997 4075. 23 J. A. Farrar R. Grinter F. Neese J. Nelson and A. J. Thomson J. Chem. Soc. Dalton Trans. 1997 4083. 24 L. Spiccia B. Graham M. T. W. Hearn G. Lazarev B. Moubaraki K. S. Murray and E. R. T. Tiekink J. Chem. Soc. Dalton Trans. 1997 4089. 25 J.-M. Teuben S. S. G. E. van Boom and J. Reedijk J. Chem. Soc. Dalton Trans. 1997 3979. 26 Z. Guo Y. Chen E. Zhang and P.J. Sadler J. Chem. Soc. Dalton Trans. 1997 4107. 27 B. Lippert J. Chem. Soc. Dalton Trans. 1997 3971 and refs. therein. 28 V. Duarte S. Sixou G. Favre G. Pratviel and B. Meunier J. Chem. Soc. Dalton Trans. 1997 4113. 29 E. Balestrieri L. Bellugi A. Boicelli M. Giomini A. M. Giuliani M. Giustini L. Marciani and P. J. Sadler J. Chem. Soc. Dalton Trans. 1997 4099. 30 S. W. A. Bligh N. Choi C. F. G. C. Geraldes S. Knoke M. McPartlin M. J. Sanganee and T. M. Woodroffe J. Chem. Soc. Dalton Trans. 1997 4119.

ISSN:1477-9226    

DOI:10.1039/dt973903

出版商:RSC    

年代:1997

数据来源: RSC