Antibiotics metal-mediated

Metal-mediated antibiotics like bleomycin, which requires iron or other metals for activity... 

Being important building blocks and versatile synthons, homoallylic alcohols are featured in the organic syntheses of many biological active molecules such as macrolides, polyhydroxylated natural products and polyether antibiotics. Among the existing means to construct these synthetically and biologically important molecules, metal-mediated Barbier-type allylation is one of the easiest and most convenient methods. 

The chemical production of hydroxyl radical, either by metal-mediated redox reactions or as a result of radiolysis products, can induce strand breaks in DNA. An example of a chemotherapeutic agent whose chemical production of activated oxygen is believed to be the critical step in its action is bleomycin, a naturally occurring antibiotic. The binding of metals to this and other antibiotics has been summarized in detail [1—3] and the material presented here is based on these reviews. 

The construction of an anthracene moiety with the help of the transition-metal-mediated alkyne cyclotrimerization reaction was exploited in the total synthesis of (+)-mbiginone B2 (58), (—)-8-0-methyltetrangomycin (59), and (-)-tetrangomycin (60), which all belong to the angucycUnone class of antibiotics isolated primarily from certain strains of bacteria (Figure 7.2) [21]. Their syntheses follow... 

A number of substances have been discovered in the last thirty years with a macrocyclic structure (i.e. with ten or more ring members), polar ring interior and non-polar exterior. These substances form complexes with univalent (sometimes divalent) cations, especially with alkali metal ions, with a stability that is very dependent on the individual ionic sort. They mediate transport of ions through the lipid membranes of cells and cell organelles, whence the origin of the term ion-carrier (ionophore). They ion-specifically uncouple oxidative phosphorylation in mitochondria, which led to their discovery in the 1950s. This property is also connected with their antibiotic action. Furthermore, they produce a membrane potential on both thin lipid and thick membranes. 

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

Kirch and Lehn have studied selective alkali metal transport through a liquid membrane using [2.2.2], [3.2.2], [3.3.3], and [2.2.C8] (146, 150). Various cryptated alkali metal picrates were transported from an in to an out aqueous phase through a bulk liquid chloroform membrane. While carrier cation pairs which form very stable complexes display efficient extraction of the salt into the organic phase, the relative rates of cation transport were not proportional to extraction efficiency and complex stability (in contrast to antibiotic-mediated transport across a bulk liquid membrane). Thus it is [2.2.Ca] which functions as a specific potassium ion carrier, while [2.2.2] is a specific potassium ion receptor (Table VI). 

As schematically own in Fig. 30, the cell membranes of living organism (/ S6) are composed of a lipid bilayer and form the interface between the intracellular and the extracellular aqueous parts. Concentrations of metal ions and amino adds in the cell are thus kept constant and the biological functions in the cell are executed. Specifically, the concentration of metal ions is in a dynamic equilibrium between the inside and the outside of the cell membrane, and it has been suggested that the mass tran rt through the membrane is mediated by lipoproteins. For the metal-km tran rt through the membrane, the participation of a group of cyclic conqxrunds called lonophores is important, which is dosely related to the antibiotic actions of cyclic peptides and cyclic depsipeptides (iJ6). These cyclic compounds are compatibile... 

The conformational studies on the ferrichromes and on ferrioxamine B indicate that a number of intramolecular hydrogen bonds are formed in the process of metal-chelation and that these contribute to the overall stability of the coordinated conformation relative to that of the free species. Consistent with this view, it should be mentioned that extensive hydrogen bonding has also been observed in the low molecular weight monovalent cation complexes of the antibiotics monensin, nigericin, dianemycin, the enniatins and valinomycin by NMR spectroscopy (69, 70), X-ray crystallography (71, 72, 73), or both. Like the siderochromes, these compounds act by mediating cation fluxes across membranes. 

Among the enniatin antibiotics, beauvericin is the one characterized in greater detail. This carrier is most interesting with respect to an anion-dependence of its transport properties Moreover, in contrast to valinomycin, it is capable of com-plexing alkaline earth as well as alkali metal ions . A study of the effects of beauvericin on the conductivity of artificial lipid membranes in the presence of both mono- and divalent cations revealed a second-order relationship between conductance and antibiotic concentration Finally, Prince, Crofts, and Steinrauf detected an apparent charge of plus one for calcium in the beauvericin-mediated transport across bacterial chromatophore membranes... 

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