Macrocyclic lipids

F.M. Monger, US Patent 5,391,726 (February 21, Assignee The Dow Chemical Company Utility Macrocyclic Lipids for Drug Delivery Agents... 

The impressive synthetic power of the McMurry couplina was demonstrated by K. Kakinuma et al. when they synthesized archaeal 72-membered macrocyclic lipids. The final macrocyclization between the dialdehyde proceeded in 66% yield, giving rise to a single diastereomer. 

Within the same context, it is worth mentioning that Menger et al. [65], Ladika et al. [66] and Moss et al. [67] have recently demonstrated that macrocyclic lipids decrease the mobility of the membrane by raising the phase transition temperature and decreasing the permeation of ionic species and the flip-flop rate. 

Syntheses of Archaebacteria 36- and 72-member macrocyclic membrane lipids (di- and tetraethers) 99YGK785. 

Ivermectin, a macrocyclic lactone, is also utilized to control parasites. An immunoassay was developed to determine ivermectin residues in bovine liver by Crooks etal. The sample preparation procedure was complex, involving tissue homogenization in acetonitrile, centrifugation, extraction with hexane (to remove lipids), evaporation and reconstitution in ethyl acetate, and passage through an SPE column followed... 

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. 

Rifampin is a semisynthetic macrocyclic antibiotic produced from Streptomyces mediterranei. It is a large lipid-soluble molecule that is bactericidal for both intracellular and extracellular microorganisms. Rifampin binds strongly to the p-subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Rifampin does not affect mammalian polymerases. 

Figure 11. (a) The chemical structure of a 24-membered macrocyclic molecule composed of alternating D- and L-amino acids, cyclo(Gln-(D-Leu-Trp)4-D-Leu 7. (b)A self-assembled tubular structure spanned across the bilayer lipid membrane. Flat ring-shaped units in the antiparallel configuration stack to form a tubular structure through extensive inter subunit hydrogen bonding and peptide side chain-lipid interactions. ... 

We have already reported that synthetic peptide lipids, having ot-amino acid residuefs) interposed between a polar head moiety and a hydrophobic doublechain segment, can be used as models for functional simulation of biomembranes [23]. On this ground, we are to clarify molecular recognition specificity by supramolecular assemblies formed in combination of the macrocyclic receptors with the peptide lipid as artificial cell-surface receptors. 

The enniatins and beauveracin are cyclic hexadepsipeptides and so are 18-membered macrocycles built up of alternating amino acid and carboxylic acid residues. They exhibit lower selectivity than (137) and consequently are more broad spectrum ionophores. The structure of (138)KI has been solved544 but it was not possible to conclude, with certainty, whether the metal is entrapped in the central cavity, as in related cyclic polyether structures (Figure 14a), or whether it occupi.es a site between two adjacent ligand molecules to give an infinite sandwich (147) as has been found in the RbNCS complex of a synthetic ldlldl isomer of (138).545 Adducts of 1 2 sandwich and 2 3 club sandwich stoichiometry have been proposed for Cs+ complexes of (138),546a and the 1 2 K+ sandwich complex of (138) has been proposed as the species which transports K+ across lipid layers as it shields the metal effectively from solvent interactions.5461 ... 

Bouquet -shaped molecules based on either a polyether macrocycle [8.205] or a /3-cyclodextrin (/3-CD) [8.206] core, such as 114 and 115 respectively, have been synthesized and their polycarboxylate forms have been incorporated into vesicle bilayer membranes [8.207]. They present structural features suitable for studies of chundle-type molecular channels (1) the functionalized cyclic annulus possesses substrate selection properties (2) it bears axially oriented bundles of oxygen-containing chains, which provide binding sites for metal cations and are long enough for the molecule to span a typical lipid membrane (the overall length with the chains... 

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... 

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