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1.
Biomater Sci ; 5(4): 741-751, 2017 Mar 28.
Article in English | MEDLINE | ID: mdl-28246669

ABSTRACT

In this work, new copolymers containing either MMA and 18C6 crown-ether pendants, or PEG, MMA and 18C6 crown-ether pendants were synthesized to test the idea that sequestering structural alkali-earth ions from the bacterial outer membrane (OM) may lead to bacterial death. The copolymers were obtained either via uncontrolled radical polymerization or ATRP; the latter approached allowed us to produce not only linear copolymers but also branched Y-like structures. After checking for the capability of complexing magnesium and calcium ions, the antimicrobial activity of all copolymers was tested placing their casted plaques in contact with pure water E. coli suspensions. All plaques adsorbed alkali-earth ions and killed bacteria, albeit with different antimicrobial efficiencies. Differences in the latter characteristic were attributed to different plaque roughness. The role of the 18C6 crown-ether pendants was elucidated by pre-saturating plaques with Mg/Ca ions, the marked reduction in antimicrobial efficiency indicating that losing the latter from OM due to surface complexation does play an important role in killing bacteria at short (<5 h) contact times. At longer times, the mode of action is instead related to the poly-cationic nature acquired by the plaques due to ion sequestering.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Crown Ethers/chemistry , Crown Ethers/pharmacology , Calcium/chemistry , Calcium/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Escherichia coli/drug effects , Escherichia coli Infections/drug therapy , Humans , Magnesium/chemistry , Magnesium/pharmacology , Methylmethacrylate/chemistry , Methylmethacrylate/pharmacology , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology
2.
Curr Med Chem ; 6(5): 415-31, 1999 May.
Article in English | MEDLINE | ID: mdl-10101221

ABSTRACT

Manoalide is a potent analgesic and antiinflammatory sesterterpene isolated in 1980 from a marine sponge. The antiinflammatory activity of manoalide is due to inhibition of PLA2, through irreversible binding to several lysine residues. The binding is realized by means of the two masked aldehyde functions present in the polar part of manoalide. Of the two aldehyde groups, only that present in the g-hydroxybutenolide ring seems to be essential, since cacospongionolides, naturally occurring analogues lacking the second masked aldehyde group, were also shown to be irreversible PLA2 inhibitors. It appears that the minimum structural requirement for exhibiting manoalide-like PLA2 inhibition would be the presence in the inhibitor of functional groups able to seize the amino groups of PLA2 lysine residues with formation of stable covalent bonds. Many manoalide analogues have been isolated from marine sponges, most of them sharing PLA2 inhibitory properties. Other interesting bioactivities have also been reported for some of these compounds.


Subject(s)
Terpenes/chemistry , Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Phospholipases A/antagonists & inhibitors , Phospholipases A2 , Structure-Activity Relationship , Terpenes/chemical synthesis , Terpenes/pharmacology
3.
J Med Chem ; 41(17): 3232-8, 1998 Aug 13.
Article in English | MEDLINE | ID: mdl-9703468

ABSTRACT

We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A2 (PLA2). The two series of compounds were tested for their inhibitory effects on secretory PLA2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addition, the PLA2 inhibitory activity increases with the increasing hydrophobic character of the side chain linked to the pyranofuranone moiety. The most active compounds, FCA and FMA, carry a farnesyl residue linked to the pyranofuranone substructure. The most potent PLA2 inhibitor, FMA, was tested in the mouse carrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to the reference antiinflammatory drug, indomethacin.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Phospholipases A/antagonists & inhibitors , Pyrans/pharmacology , Terpenes/chemical synthesis , Terpenes/pharmacology , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bee Venoms , Carrageenan , Cell Line , Cytosol/enzymology , Drug Design , Edema/chemically induced , Edema/drug therapy , Elapid Venoms , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Kinetics , Mice , Molecular Structure , Pancreas/enzymology , Phospholipases A2 , Structure-Activity Relationship , Swine , Synovial Membrane/enzymology , Terpenes/chemistry
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