Enterobactin (3), the iron-binding ionophore of the enteric bacteria, has been synthesized from L-serine. The antipode of the natural product, enantioenterobactin (42), has been analogously assembled from D-serine, and the iron-binding and biological properties of the ligand have been investigated. Linear, chiral analogue 66 has been synthesized from L-asparagine, and the analogue Fe(II1) complex 67 has been characterized. Attempts to assemble the trilactam analogue 4 have failed at the cyclization step.To contend with the insolubility of ferric hydroxide in an aqueous milieu [K,,(Fe(OH)3) = microbes have evolved specialized ligands or siderophores3 to acquire and transport environmental iron into the cell. The siderophores bind Fe(II1) by wrapping six ligating atoms around the metal center in either a right-handed (A) or left-handed (A) coordination propeller (see enantiomeric complexes 1 and 2). We have assumed that the chirality of an iron-
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The binding of [3H]-Cyclopentyladenosine (CPA), an N6-substituted analog of adenosine, was examined in vitro. CPA bound with high affinity (Kd = 0.48 nmol/l) to rat brain membranes. Specific binding, which represented 90-97% of the total counts bound at a ligand concentration of 1 nmol/l, was saturable, reversible and sensitive to protein denaturation. The pharmacology of binding was consistent with the labeling of an A-1 receptor, the R- and S-diasteromers of N6-phenylisopropyladenosine (PIA) showing a sixteenfold difference in their ability to displace CPA. The prototypic A-1 selective adenosine agonist, N6-cyclohexyladenosine (CHA) was twofold less active than CPA in displacing radiolabeled CPA. Comparison of the ability of cold CHA and CPA to displace [3H]-CPA gave rate dissociation constants of 1.88 and 1.80 X 10(4) s-1, respectively suggesting that both CHA and CPA bound to the same recognition site. In contrast however, comparison of the binding of [3H]-CPA with that of [3H]-CHA showed distinct differences. The Kd for CHA was approximately twice that of CPA while the apparent Bmax was 60% greater. In comparing the pharmacology of CPA binding with that of CHA, it was found that CHA, S-PIA and the antagonist, PACPX were more active in displacing CHA than CPA. In general however, CPA has a binding profile very similar to that observed with CHA.
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