Antibiotics metal complexes

Bleomycin Antibiotics Metal Complexes and Their Biological Action... 

Olstein, A. D. Feirtag, J. M. Antibiotic-metal complexes in the detection of gram-negative bacteria and other biological analytes. PCT Int. Appl. WO 2001027628, 2001 Chem. Abstr. 2001, 134, 307594. 

Anthraquinone, 1-hydroxy-calcium aluminum chelate compound, 1,2 metal complexes dyes, 6,86 Antiarthritis drugs labelled gold compounds, 6, 969 metal complexes, 6,758 Antibiotic M139163,2, 974 Antibiotics ionophoric, 6, 553 metal complexes selective binding, 6, 552... 

There are two general classes of naturally-occurring antibiotics which influence the transport of alkali metal cations through natural and artificial membranes. The first category contains neutral macrocyclic species which usually bind potassium selectively over sodium. The second (non-cyclic) group contains monobasic acid functions which help render the alkaline metal complexes insoluble in water but soluble in non-polar solvents (Lauger, 1972 Painter Pressman, 1982). The present discussion will be restricted to (cyclic) examples from the first class. 

The symmetrical ring enniatin (304) forms a potassium complex (Figure 9.3) whose crystal structure indicates that the cation is contained in the macrocyclic cavity and is coordinated by the six carbonyl oxygen atoms which are orientated such that three lie above and three lie below the main plane of the molecule (Dobler, Dunitz Krajewski, 1969). Apart from those just discussed, it needs to be noted that a range of other structures of antibiotic molecules and their metal complexes have been determined (Hilgenfeld Saenger, 1982). 

Many chiral compounds can be used as selectors, for example, chiral metal complexes, native and modified cyclodextrins, crown ethers, macrocyclic antibiotics, noncyclic oligosaccharides, and polysaccharides all have been shown to be useful for efficient separation of different types of compounds. 

Oxygen activation has been shown to be important both in the presumed mechanism of attack on DNA by metal complexes of antibiotics, and in the synthesis of dexoyribonucleotides from the corresponding ribonucleotides. Although primarily centered on iron complexes, and thus outside of the scope of this review, some cobalt analogue complexes have been discussed. 

Figure 31 Schematic representations of some metal complexes of acid antibiotics (reproduced with permission from...

Heavier metal ions and metal complexes can find sites on nitrogen atoms of the nucleic acid bases. Examples are the platinum complex cisplatin and the DNA-cleaving antibiotic neocarzinostatin (Box 5-B). Can metals interact with the n electrons of stacked DNA bases A surprising result has been reported for intercalating complexes of ruthenium (Ru) and rhodium (Rh). Apparent transfer of electrons between Ru (II) and Rh (III) over distances in excess of 4.0 nm, presumably through the stacked bases, has been observed,181 as has electron transfer from other ions.181a Stacked bases are apparently semiconductors.182... 

Ionophores, or polyether (PET) antibiotics, produced by various species of Streptomyces, possess broad spectrum anticoccidial activities. They are chemically characterized by several cyclic esters, a single terminal carboxylic acid group, and several hydroxyl groups. Representative members of this class include salinomycin (SAL), monensin (MON), lasalocid (LAS), narasin (NAR), maduramicin (MAD), and semduramicin (SEM). The main chemical properties of interest in the extraction methodology are their low polarities and instability under acidic conditions. They are able to form stable complexes with alkaline cations. All of these compounds, with the exception of LAS, bind monovalent cations (e.g., Na+ and K+). Lasalocid has a tendency to form dimers and can form complexes with divalent cations such as Mg2+ and Ca2+. The formation of metal complexes results in all of these compounds adopting a quasi-cyclic formation consequent to head-to-tail hydrogen bonding. No MRLs have yet been set by the EU for any of the carboxylic acid PETs (98). 

It seems likely that the future will see major developments in the use of metal complexes as bacteriocidal, viricidal, immunosuppressive, anti-arthritic and biocidal agents. One class of complexing agents that appears to have particular promise are the macrocyclic antibiotics, macrocyclic polyethers, polyamines and cryptates . In this group the ligand wraps around a metal ion to form a lipid-soluble complex... 

The bleomycins (Fig. 12.6) are a family of glycopeptide-derived antibiotics which are used in the treatment of various tumors. They bind iron in the blood and form an active hypervalent oxo-iron species. The two-dimensional structure is well known but no crystal structures of bleomycin or its metal complexes have been reported. The MM2 force field was modified and extended by modeling of the crystal structures of the cobalt complexes of two bleomycin analogues in order to develop a force field for... 

Until the late 1960s, whereas there had been considerable interest in the transition metal complexes of natural and synthetic macrocyclic ligands (1—4), relatively few reports described complexes of alkaline earth and more particularly alkali metal cations. Research in this area was stimulated by the recognition of the importance of the biological role of Na+, K, Ca2 , and Mg2 and also the discovery and characterization of the natural antibiotic ionophores (5, 6). These macrocyclic antibiotics, such as valinomycin and nonactin, were shown to complex alkali metal cations with remarkable selectivity (7-9). 

Barber et al. (61) have used FAB to study the antibiotics bleomycin A2 and B2 and their metal complexes. In particular, the ferrous sulfate complex of bleomycin A2 shows a pseudomolecular ion at mlz 1566, corresponding to the salt (A2 - H+ + FeS04) since the amide hydrogen of the histidine residue is lost on complexation. An ion at mlz 472 corresponds to the ferrous ion complexed to the surrounding ligands but lacking the disaccharide groups and the peptide chain. 

The types of alkali and alkaline earth metal complexes subjected to molecular mechanics modeling fall into four categories crown ethers[U9,486 491], cryp-tands[492 493], spherands[494,495], and other biologically important ligands, such as ionophores and cyclic antibiotics [496 499]. 

In order to utilize such a chiral substructure as a source of absolute stereoehemical information in a synthesis, it is necessary to employ the complexes A and ent-A in non-racemie form. While the enan-tioselective preparation of such chiral complexes was achieved in the past more or less exclusively via resolution of raeemic mixtures, the diastereo-selective complexation of chirally modified ligands was shown more recently to be a practical alternative [2]. Another possibility, the enantiose-lective conversion of prochiral metal complexes by means of chiral reagents, has been achieved by W. R. Roush 3]. In a remarkable (formal) total synthesis of the antibiotic (-i-)-ikarugamycin (1), Roush et al. apply their method and demonstrate in a highly convincing fashion the synthetic usefulness of acyclic butadiene-FefCOfj complexes [4]. 

In addition to the above examples, there are still a large number of bioactive natural products and various synthetic and semisynthetic enol-containing compounds that serve as potential and promising drugs for various therapeutic purposes such as the non-peptidyl HIV inhibitor Aptivus (tipranavir Section IV.1) and the third-generation tetracycline antibiotics (Section IV.H). The structure and function of the metal complexes of some... 

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