Aluminium has been known as a neurotoxic agent to experimental animals since the last century (Arch. Exp. Pharmacol. 40 (1897) 98). However, great interest arose in it bioinorganic chemistry as well biology when it was demonstrated to be the causative agent in pathologies related to the long-term dialysis treatment of uremic subjects with renal failure (Life Chem. 11 (1994) 197), and as a potential etiopathogenic cofactor for several neurodegenerative diseases. The inorganic biochemistry of aluminium is still largely to be discovered. In this review the pro-oxidative property of aluminium toward biological membrane will be presented and its implications in involvement in human pathology will be discussed in an interdisciplinary frame from the bioinorganic point of view.

Among a series of newly synthesised chiral aminomethylpyrrolidines, the 2-benzyl-substituted derivative was recently recognised as a possible precursor of copper(II) ligands with .OH-scavenging properties. In a preliminary attempt to characterise the structure of the copper(II) complexes of this type of ligand, formation complex equilibria of the copper(H) ion with the [S] and [R] enantiomers of the parent 2-benzylaminomethylpyrrolidine have been investigated at 37°C in 0.15 mol dm−3 NaClO4 using glass electrode potentiometry, UV-Vis spectrophotometry and circular dichroism. Two main complexes have been found, ML and ML2, with appreciable stabilities compared to their copper(H) homologues of histidine, the predominant low-molar-mass ligand of copper(II) in blood plasma. These species are also characterised by clear Cotton effects. Possible structures are discussed.

As a "hard", trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such as citrate and phosphate. The aqueous coordination chemistry of Al is complicated by the tendency of many Al complexes to hydrolyze and form polynuclear species, many of which are sparingly soluble. Thus there is considerable variation among the Al stability constants reported for several important ligands. The complexity in the aqueous chemistry of Al has also affected Al toxicity studies, which have often utilized poorly characterized Al stock solutions. Serum fractionation studies show that most Al is protein bound, primarily to the serum iron transport protein transferrin. Albumin appears to play little, if any, role in serum transport. There is little agreement as to the speciation of the remaining low-molecular mass fraction of serum Al. The lability of the Al3+ion precludes the simple separation and identification of individual Al complexes. Computational methods are available for detailed computer calculations of the Al speciation in serum, but efforts in this area have been severely hampered by the uncertainties regarding the stability constants of the low molecular mass Al complexes with citrate, phosphate, and hydroxide. Specific recommendations for further research on Al speciation include: (1) Determine more accurate Al stability constants with critical low molecular mass ligands such as citrate and phosphate; (2) supplement traditional potentiometric studies on Al complexes with data from other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al; (3) develop new methods for generating reliable linear free energy relationships for Al complexation; (4) determine equilibrium and rate constants for Al binding to transferrin at 37 degrees C; (5) confirm the possible formation of low-molecular-mass Al-protein complexes following desferrioxamine therapy; (6) continue research efforts to incorporate kinetic considerations into the present equilibrium speciation calculations; (7) improve methods for preparing chemically well-defined stock solutions for toxicological studies; (8) incorporate more detailed speciation data into studies on Al toxicity and pharmacokinetics; and (9) incorporate more detailed speciation data into future epidemiological studies on the relationship between Al toxicity and various water quality parameters.

The present work examines the different binding modes of the Cu2+ ion in its complexes with three bioactive tetracycline antibiotics: tetracycline, oxytetracycline, and chlortetracycline (similar studies with doxycline were prevented by precipitation problems). Spectroscopic investigations involving UV-visible absorption and circular dichroism techniques have been used under predetermined conditions of concentrations and pH so that species successively formed in each system could be selectively investigated. Copper interactions with structurally simpler analogs (4-(dedimethylamino)tetracycline and 6-desoxy-6-demethyltetracycline) were also studied as references, which required the determination of corresponding complex formation constants. For all bioactive analogs including 6-desoxy-6-demethyltetracycline, it is shown that the first donor group to bind copper is the O3 atom, which starts deprotonating at relatively low pH, with MLH-2 as the resulting species. When the pH is raised, MLH progressively substitutes for MLH-2, Chelation then taking place at the O10-O12 system as the OH12 group dissociates. The ultimate ligand deprotonation at the C4 dimethylammonium group leads to the formation of ML, with a new change in the binding mode in favor of the N4-OH12a donor set. Concerning the 1:2 metal-to-ligand complexes which coexist with the above species, ML2H-4 is logically bound in the MLH-2 manner, whereas ML2H-2, ML2H, and ML2 adopt an identical coordination scheme in which alternate bonds are presumed to be formed at both the O10-O12 juncture and the N4-O12a pinch. The present work further substantiates Albert's former view of a possible influence of metal ions on the pharmacological action of tetracyclines. Following the recent evidence of the important roles of calcium and magnesium in the transport of these drugs in blood plasma, it is now suggested here that copper can act as a cofactor of their antibiotic activity: first, the structural flexibility of copper binary complexes within the three distinct donor sites of bioactive tetracyclines is expected to favor mixed-ligand coordination with bacterial nucleic acids; then, through the formation of such ternary complexes, copper may induce the attack of free radicals known to damage these nucleic acids.

Previous studies based on computer-simulated distributions of several tetracyclines in blood plasma during treatment have revealed that the fraction of drug not bound to proteins almost exclusively occurs in the form of calcium and magnesium complexes. In contrast to former thoughts, it thus appeared that the bioavailability of tetracyclines should primarily depend on the physicochemical properties of the most predominant of these species rather than on those of the free patent molecules. In particular, the possible formation of electrically charged homo- or heterobinuclear complexes with the above two metals at the expense of their neutral diffusible mononuclear homologues should notably reduce the bioavailability of the drug.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMetal ion-tetracycline interactions in biological fluids. 9. Circular dichroism spectra of calcium and magnesium complexes with tetracycline, oxytetracycline, doxycycline, and chlortetracycline and discussion of their binding modesLuc Lambs, Brigitte Decock-Le Reverend, Henryk Kozlowski, and Guy BerthonCite this: Inorg. Chem. 1988, 27, 17, 3001–3012Publication Date (Print):August 1, 1988Publication History Published online1 May 2002Published inissue 1 August 1988https://pubs.acs.org/doi/10.1021/ic00290a022https://doi.org/10.1021/ic00290a022research-articleACS PublicationsRequest reuse permissionsArticle Views1000Altmetric-Citations74LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Effects of metal ion-tetracycline (TC) interactions on both gastrointestinal absorption and pharmacological activity of these drugs are well documented. In particular, recent simulation studies based on newly determined complex stability constants have drawn attention to the potential influence of Ca2+ and Mg2+ ions on the bioavailability of various TC derivatives in blood plasma. Contrary to previous thoughts, it was demonstrated in these studies that the fraction of antibiotic not bound to proteins almost exclusively occurs as calcium and magnesium complexes. Among this fraction, predominant binuclear species are electrically charged, and as such cannot passively diffuse through cell membranes. It was thus postulated that the partial blocking of one of the potential coordination sites of the TC molecule, which would favor the formation of neutral mononuclear complexes, should result in a better tissue penetration of the drug. Such correlations were recently established for specific derivatives.

ChemInformVolume 19, Issue 51 Physical Organic Chemistry ChemInform Abstract: Metal Ion-Tetracycline Interactions in Biological Fluids. Part 9. Circular Dichroism Spectra of Calcium and Magnesium Complexes with Tetracycline, Oxytetracycline, Doxycycline, and Chlortetracycline and Discussion of Their Binding Modes. L. LAMBS, L. LAMBS INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorB. DECOCK-LE REVEREND, B. DECOCK-LE REVEREND INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorH. KOZLOWSKI, H. KOZLOWSKI INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorG. BERTHON, G. BERTHON INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this author L. LAMBS, L. LAMBS INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorB. DECOCK-LE REVEREND, B. DECOCK-LE REVEREND INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorH. KOZLOWSKI, H. KOZLOWSKI INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this authorG. BERTHON, G. BERTHON INSERM, Univ. Paul Sabatier, 31400 Toulouse, Fr.Search for more papers by this author First published: December 20, 1988 https://doi.org/10.1002/chin.198851053AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue51December 20, 1988 RelatedInformation

Associations of Mg2+ ions with organic ligands are frequently advertised as likely to enhance the bioavailability of magnesium from orally administered commercial preparations. However, no systematic study of the relevant equilibria has been produced so far to substantiate these assertions, and no superiority has yet been demonstrated for any magnesium salt on clinical grounds.

The biological activity of thymulin, a recently discovered metallo-nonapeptide, has been shown to be essentially zinc dependent.

Following a recent investigation into cimetidine interactions with copper(II) and zinc(II), the present work deals with the study of coordination equilibria relative to the main metabolite of this drug, i.e. cimetidine sulfoxide, with the same metal ions under physiological conditions.

A series of studies was previously devoted to the dependence of the bioavailability of various tetracyclines on their coordination with calcium and magnesium ions. Several clinical investigations have also shown zinc to interfere with the gastrointestinal absorption of the drug in humans. On the other hand, the administration of tetracycline to rats was reported to result in the increase of the elimination rate of zinc, which could orginate in zinc-tetracycline interactions in blood plasma.

Coordination of tetracydines with calcium and magnesium was previously shown to exert a determining effect on the distribution of these antibiotics in blood plasma. In particular, it was clearly established by computer simulation that the free fraction of the drug is quite negligible with respect to its metal-bound fraction. The bioavailabiity of a tetracycline in blood plasma is thus expected to depend directly on the electrical charge of its predominant metal complexes in the biofluid. On account of the metal to ligand ratio corresponding to the usual therapeutic levels, bioavailability is critically sensitive to the property of the antibiotic to give rise to electrically charged binuclear species. The blocking of one of the two potential binding sites of the tetracycline molecule should thus result in a larger percentage of neutral complexes, hence in a better tissue penetration by the drug.

The hypothesis was formerly put forward that the main therapeutic action of cimetidine (the histamine H2-receptor antagonist marketed as Tagamet®) as well as some of its side effects might be mediated by its interactions with essential metal ions.

Les équilibres de coordination du polyphosphate de doxycycline (Doxycline R) avec les ions H+, Ca2+ et Mg2+ ont été étudiés par voie potentiométrique è 37°C en milieu NaCl 0,15 M. La distribution de l’antibiotique dans les conditions thérapeutiques a été simulée quantitativement (i) dans le plasma sanguin, (ii) dans le fluide gastro-intestinal en absence et en présence de calcium.

equilibrium constants for the complexes formed between the calcium ion and a series tetracyclines, i.e. tetracycline, oxytetracycline, doxycycline, minocycline, were protentiometrically determined at 37°C in aqueous medium NaCl 0.15 mol dm−3. The distribution of the complexes was then simulated under physiological conditions at therapeutic levels of the drugs. Results are discussed concerning the possible effect of the calciumtetracyclines interactions regarding the mode of action and the distribution of these antibiotics in the human body.

A new computer-based approach has been developed to assess the optimal doses of essential trace metal ions which should be included in nutritive mixtures, used in human total parenteral nutrition, to compensate for the ligand-induced losses of these metal ions. An example of application is given for zinc, copper and manganese.

Vaporization enthalpies of piperidine, N-methylpiperidine, 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, and 2,6-dimethylpiperidine were determined by means of vapor-pressure measurements. Their combination with the solution enthalpies of these amines in the 0.5 mol dm −3 of KNO 3 aqueous medium at 298.15 K led to the calculation of the corresponding solvation enthalpies. Comparing the latter with the protonionization enthalpies earlier obtained under the same experimental conditions enables us to confirm the observation made in a previous paper of the exclusive influence of solvent effects upon proton-ionization thermodynamic functions. In effect, except for N-methylpiperidine, the solvation enthalpies of the piperidinium ions are shown to be proportional to those of the neutral piperidines. This result implies (except for the N position) that the variation of position of the methyl group affects the solvation of the substituted piperidinium ions only through the hydrophobic interactions with the solvent, but not because of a change in the distribution of the electrical charge inside the ion. This confirms the absence of an electrical-substituent effect.