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1.
Bioorg Med Chem Lett ; 23(18): 5165-9, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23916260

ABSTRACT

The influenza A virus (IFV) possesses a highly ordered cholesterol-rich lipid envelope. A specific composition and structure of this membrane raft envelope are essential for viral entry into cells and virus budding. Several steroidal amines were investigated for antiviral activity against IFV. Both, a positively charged amino function and the highly hydrophobic (ClogP≥5.9) ring system are required for IC50 values in the low µM range. An amino substituent is preferential to an azacyclic A-ring. We showed that these compounds either disrupt or augment membrane rafts and in some cases inactivate the free virus. Some of the compounds also interfere with virus budding. The antiviral selectivity improved in the series 3-amino, 3-aminomethyl, 3-aminoethyl, or by introducing an OH function in the A-ring. Steroidal amines show a new mode of antiviral action in directly targeting the virus envelope and its biological functions.


Subject(s)
Amines/pharmacology , Antiviral Agents/pharmacology , Influenza A virus/drug effects , Membrane Microdomains/drug effects , Amines/chemical synthesis , Amines/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Conformation , Structure-Activity Relationship
2.
Eur J Med Chem ; 46(6): 2147-51, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21421276

ABSTRACT

The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications in cancer and leishmaniasis, miltefosine has also been shown to block immunoglobulin E receptor-dependent mast cell activation. Miltefosine and other alkylphospholipids that are active in mast cell degranulation assays contain a positively charged nitrogen and a phosphate group that are important for activity. In addition to alkylphospholipids, ceramides are also known to act on membrane environments and inhibit mast cell activation. We have systematically searched a very large compound collection for other lipid-like inhibitors of mast cell activation. Analogs of an initially identified screening hit were synthesized and preliminary SAR information was collected, leading to the identification of sulfoxide and amine oxide containing lipid-like compounds as new inhibitors of mast cell activation. Sulfoxide and amine oxide derivatives were found to be only slightly less active than miltefosine.


Subject(s)
Amines/pharmacology , Mast Cells/drug effects , Oxides/pharmacology , Sulfoxides/pharmacology , Amines/chemical synthesis , Amines/chemistry , Animals , Dose-Response Relationship, Drug , Mast Cells/metabolism , Molecular Structure , Oxides/chemical synthesis , Oxides/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/chemistry
3.
Eur J Med Chem ; 45(6): 2700-4, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20153565

ABSTRACT

Receptor-mediated signaling events frequently depend on the integrity of their membrane environments. Only a limited number of compounds are currently available that are known or thought to modulate membrane environments and affect signaling events without disrupting membrane structure. Among these are alkylphospholipids including the drug miltefosine that is approved for the treatment of breast cancer and leishmaniasis. In addition, miltefosine has recently been shown to block immunoglobulin E receptor-dependent mast cell activation. On the basis of these findings, we have explored other alkylphospholipids as potential inhibitors of mast cell activation and confirmed the inhibitory activity of five molecules. By comparing the head groups of these alkylphospolipids common pharmacophore features were determined. Through computational screening utilizing this pharmacophore information a new lipid-like inhibitory chemotype was identified that blocked mast cell activation with potency comparable to miltefosine.


Subject(s)
Cell Membrane/metabolism , Computational Biology , Drug Evaluation, Preclinical/methods , Mast Cells/cytology , Mast Cells/drug effects , Animals , Cell Degranulation/drug effects , Cell Line, Tumor , Computer Simulation , Models, Molecular , Molecular Conformation , Rats
4.
Science ; 320(5875): 520-3, 2008 Apr 25.
Article in English | MEDLINE | ID: mdl-18436784

ABSTRACT

beta-Secretase plays a critical role in beta-amyloid formation and thus provides a therapeutic target for Alzheimer's disease. Inhibitor design has usually focused on active-site binding, neglecting the subcellular localization of active enzyme. We have addressed this issue by synthesizing a membrane-anchored version of a beta-secretase transition-state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active beta-secretase found in endosomes and also reduced the dimensionality of the inhibitor, increasing its local membrane concentration. This inhibitor reduced enzyme activity much more efficiently than did the free inhibitor in cultured cells and in vivo. In addition to effectively targeting beta-secretase, this strategy could also be used in designing potent drugs against other membrane protein targets.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Endosomes/enzymology , Peptides/pharmacology , Protease Inhibitors/pharmacology , Sterols , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Animals, Genetically Modified , Drosophila/genetics , Drug Delivery Systems , Endocytosis , HeLa Cells , Humans , Intracellular Membranes/metabolism , Membrane Microdomains/enzymology , Mice , Peptides/chemistry , Peptides/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism
5.
Org Lett ; 7(21): 4573-6, 2005 Oct 13.
Article in English | MEDLINE | ID: mdl-16209482

ABSTRACT

[reactions: see text] Two complementary and efficient strategies have been developed for the regiospecific synthesis of unsymmetrical indolopyrrolocarbazoles (IPCs) mono-N-substituted with a pentacycle. A halogen in position 2 of the intermediate bisindolylmaleimides 3a-e allows a selective Mitsunobu coupling by exploiting the increased acidity of the 2-chloro-substituted indole nitrogen. It also promotes an easier cyclization of bisindolylmaleimides 4a-e and 7b-e to IPCs. Alkylation of the 2-unsubstituted indole-3-carboxamides 2a,b and further processing to the corresponding IPCs gives access to the opposite regioisomers.


Subject(s)
Carbazoles/chemical synthesis , Glycosides/chemical synthesis , Alkylation , Carbazoles/chemistry , Cyclization , Glycosides/chemistry , Molecular Structure , Stereoisomerism
6.
Chemistry ; 8(6): 1300-9, 2002 Mar 15.
Article in English | MEDLINE | ID: mdl-11921213

ABSTRACT

A library of "tweezer" receptors, incorporating a guanidinium "head group" and two peptide derived side arms has been prepared on the solid-phase using an orthogonally protected guanidinium scaffold 12. The library was screened with various tripeptide derivatives in an aqueous solvent system. A tweezer receptor 25 for the side chain protected tripeptide 19 was identified from the screening experiments. Receptor 25 was resynthesised and solution binding studies were carried out, which revealed that 25 binds to tripeptide 19 with K(a)=8.2 x 10(4) +/- 2.5 x 10(4) (15 % DMSO/H(2)O, pH 8.75) and with appreciable selectivity over the tripeptide enantiomer 22 and the side chain deprotected tripeptide 20.


Subject(s)
Guanidine/chemistry , Peptide Library , Receptors, Peptide/chemistry , Combinatorial Chemistry Techniques , Models, Chemical , Solutions , Substrate Specificity , Water
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