Interaction of cationic amphiphilic drugs with lipid A: Implications for development of endotoxin antagonists

This report presents evidence for the interactions of several classes of cationic amphiphilic drugs including the phenothiazines, aminoquinolines, biguanides, and aromatic diamidines, with lipid A, the endotoxic principle of lipopolysaccharides. The interactions of the drugs were quantitatively assessed by fluorescence methods. The affinities of the drugs for lipid A parallel their endotoxin-antagonistic effects in the Limulus gelation assay. Dicationic compounds bind lipid A with greater affinity; the affinity of such molecules increases exponentially as a function of the distance between the basic moieties. The bis-amidine drug - pentamidine - examined in greater detail, binds lipid A with high affinity (apparent K-d: 0.12 mu M), and LPS, probably due to simultaneous interactions of the terminal amidine groups with the anionic phosphates on lipid A. The sequestration of endotoxin by pentamidine reduces its propensity to bind to cells, and the complex exhibits attenuated toxicity in biological assays. These results have implications in the development of therapeutic strategies against endotoxin-related disease states.

Nucleophilic attacks of 1,2-diaminoethane on MeCN ligands: synthesis, x-ray structure, and spectral and electrochemical properties of [Ru(.mu.-O)(.mu.-O2CAr)2[NH2CH2CH2NHC(Me)NH]2(PPh3)2](ClO4)2(Ar = C6H4-p-X; X = H, Me, OMe, Cl)

The diruthenium(III) complex [Ru2O(O2CAr)2(MeCN)4(PPh3)2](ClO4)2 (1), on reaction with 1,2-diaminoethane (en) in MeOH at 25-degrees-C, undergoes nucleophilic attacks at the carbon of two facial MeCN ligands to form [(Ru2O)-O-III(O2CAr)2-{NH2CH2CH2NHC(Me)NH}2(PPh3)2](ClO4)2 (2) (Ar = C6H4-p-X, X = H, Me, OMe, Cl) containing two seven-membered amino-amidine chelating ligands. The molecular structure of 2 with Ar = C6H4-p-OMe was determined by X-ray crystallography. Crystal data are as follows: triclinic, P1BAR, a = 13.942 (5) angstrom, b = 14.528 (2) angstrom, c = 21.758 (6) angstrom, alpha = 109.50 (2)-degrees, beta = 92.52 (3)-degrees, gamma = 112.61 (2)-degrees, V = 3759 (2) angstrom 3, and Z = 2. The complex has an {Ru2(mu-O)(mu-O2CAr2)2(2+)} core. The Ru-Ru and average Ru-O(oxo) distances and the Ru-O-Ru angle are 3.280 (2) angstrom, 1.887 [8] angstrom, and 120.7 (4)-degrees, respectively. The amino group of the chelating ligand is trans to the mu-oxo ligand. The nucleophilic attacks take place on the MeCN ligands cis to the mu-oxo ligand. The visible spectra of 2 in CHCl3 display an absorption band at 565 nm. The H-1 NMR spectra of 2 in CDCl3 are indicative of the formation of an amino-amidine ligand. Complex 2 exhibits metal-centered quasireversible one-electron oxidation and reduction processes in the potential ranges +0.9 to +1.0 V and -0.3 to -0.5 V (vs SCE), respectively, involving the Ru(III)2/Ru(III)Ru(IV) and Ru(III)2/Ru(II)Ru(III) redox couples in CH2Cl2 containing 0.1 M TBAP. The mechanistic aspects of the nucleophilic reaction are discussed.