Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Antimicrob Agents Chemother ; 56(10): 5149-56, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22825118

ABSTRACT

Type III phosphatidylinositol-4-kinase beta (PI4KIIIß) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIß inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIß in lymphocyte proliferation. Previously proposed functions of PI4KIIIß in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIß inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.


Subject(s)
1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Animals , Antiviral Agents/adverse effects , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Humans , Male , Mice , Rats , Rats, Sprague-Dawley
2.
Antimicrob Agents Chemother ; 56(8): 4463-5, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22644023

ABSTRACT

LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.


Subject(s)
Clostridioides difficile/drug effects , Clostridioides difficile/genetics , Peptide Chain Elongation, Translational/drug effects , Peptide Elongation Factor Tu/genetics , Thiazoles/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Binding Sites/genetics , Drug Resistance, Bacterial/genetics , Enterocolitis, Pseudomembranous/drug therapy , Enterocolitis, Pseudomembranous/microbiology , Humans , Microbial Sensitivity Tests , Protein Structure, Tertiary
3.
Antimicrob Agents Chemother ; 55(11): 5277-83, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21825297

ABSTRACT

Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Peptide Elongation Factor Tu/antagonists & inhibitors , Thiazoles/therapeutic use , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cell Line , Cell Survival/drug effects , Female , Hep G2 Cells , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , Peptides, Cyclic/chemistry , Staphylococcal Infections/drug therapy , Thiazoles/adverse effects , Thiazoles/chemistry , Thiazoles/pharmacology
4.
Chem Biol ; 8(9): 843-55, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11564553

ABSTRACT

BACKGROUND: During the past decade, Taxol has assumed an important role in cancer chemotherapy. The search for novel compounds with a mechanism of action similar to that of Taxol, but with greater efficacy particularly in Taxol-resistant cells, has led to the isolation of new natural products. One such compound, (+)-discodermolide, although structurally distinct from Taxol, has a similar ability to stabilize microtubules. In addition, (+)-discodermolide is active in Taxol-resistant cell lines that overexpress P-glycoprotein, the multidrug-resistant transporter. Interestingly, (+)-discodermolide demonstrates a profound enhancement of the initiation process of microtubule polymerization compared to Taxol. RESULTS: The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity relationship (SAR) studies. Small changes to the (+)-discodermolide structure resulted in a dramatic decrease in the ability of all four discodermolide analogs to initiate tubulin polymerization. Two of the analogs also demonstrated a decrease in total tubulin polymerization, while a change in the olefin geometry at the C8 position produced a significant decrease in cytotoxic activity. CONCLUSIONS: The availability of (+)-discodermolide and the analogs, and the resultant SAR analysis, have permitted an exploration of the similarities and differences between (+)-discodermolide and Taxol. Docking of the X-ray/solution structure of (+)-discodermolide into the Taxol binding site of beta-tubulin revealed two possible binding modes (models I and II). The preferred pharmacophore model (I), in which the C19 side chain of (+)-discodermolide matches with the C2 benzoyl group of Taxol and the delta-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis.


Subject(s)
Alkanes , Antineoplastic Agents, Phytogenic/pharmacology , Carbamates , Lactones/pharmacology , Paclitaxel/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Binding, Competitive , Flow Cytometry , Humans , Inhibitory Concentration 50 , Lactones/chemical synthesis , Lactones/chemistry , Microscopy, Electron , Microscopy, Fluorescence , Microtubules/drug effects , Models, Molecular , Paclitaxel/chemistry , Pyrones , Stereoisomerism , Structure-Activity Relationship , Tubulin/drug effects , Tumor Cells, Cultured
5.
Org Lett ; 3(5): 695-8, 2001 Mar 08.
Article in English | MEDLINE | ID: mdl-11259039

ABSTRACT

[structure: see text]. The solution structure of (+)-discodermolide (1) has been determined via 1- and 2-D NMR techniques in conjunction with Monte Carlo conformational analysis. Taken together, the results demonstrate that in solution (+)-discodermolide occupies a helical conformation remarkably similar to the solid state conformation.


Subject(s)
Alkanes , Carbamates , Immunosuppressive Agents/chemistry , Lactones/chemistry , Porifera/chemistry , Animals , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Monte Carlo Method , Pyrones , Solutions , Tubulin/chemistry
6.
Org Lett ; 1(11): 1823-6, 1999 Dec 02.
Article in English | MEDLINE | ID: mdl-10836041

ABSTRACT

[formula: see text] A triply convergent, highly efficient second-generation synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on a 1-g scale.


Subject(s)
Alkanes , Antineoplastic Agents/chemical synthesis , Carbamates , Lactones/chemical synthesis , Animals , Indicators and Reagents , Porifera/chemistry , Pyrones , Stereoisomerism
SELECTION OF CITATIONS
SEARCH DETAIL
...