ABSTRACT
A new series of antimicrobial derivatives [3-(4,5-diaryl-1H-imidazol-2-yl)-1H-indole)] have been synthesized with potent activity against strains of Staphylococcus aureus, including methicillin-resistant strains (MRSA). Compound 17 [3-(4,5-bis(4-fluorophenyl)-1H-imidazol-2-yl)-5-bromo-1H-indole], the most active derivative was shown to inhibit the growth of all Gram-positive strains tested, including vancomycin resistant Enterococcus faecalis and Enterococcus faecium with no activity against Gram-negative bacteria.
Subject(s)
Anti-Infective Agents/chemical synthesis , Indoles/chemical synthesis , Indoles/pharmacokinetics , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Infective Agents/pharmacology , Enterococcus faecalis/drug effects , Enterococcus faecium/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Vancomycin/pharmacologyABSTRACT
PURPOSE: A cholesterol-free liposome formulation formed from mixtures of egg phosphatidylcholine (ePC) and poly (ethylene glycol) conjugated distearoylphosphatidylethanolamine (DSPE-PEG 2000) was optimized and evaluated for delivery of a novel anti-cancer agent ML220 (2-(5-bromo-1H-indol-3-yl)-1H-phenanthro [9,10-d] imidazole). RESULTS AND DISCUSSION: ML220 is highly lipophilic with a water solubility of 0.14 mug/ml and calculated log P of 5.69. The ML220-loaded liposomes had a unimodal size-distribution and a mean diameter of 89 nm. The drug to lipid ratio in the formulation was 1:3.5 (mol:mol) and the drug loading efficiency was 83% providing a more than 50,000-fold increase in the water solubility of ML220. The formulation was demonstrated to be stable in vitro at 37 degrees C for over 2 weeks with a delayed drug release profile. Evaluation of the subacute toxicity of the liposome formulated drug in C3H mice revealed no overt signs of toxicity. Also, a biexponential drug plasma concentration pattern was found upon evaluation of the pharmacokinetics in Balb/C mice. The in vivo evaluation of the anti-cancer activity in a human colon HT29 carcinoma model revealed a significant delay in tumor growth. CONCLUSION: Overall, the ePC/DSPE-PEG liposomes were demonstrated to be a suitable delivery system for ML220. These studies also highlight the potential of cholesterol-free liposomes as a formulation strategy for highly lipophilic drugs.
Subject(s)
Antineoplastic Agents , Neoplasms, Experimental/drug therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Drug Compounding , Drug Screening Assays, Antitumor , Drug Stability , Female , Humans , Hydrophobic and Hydrophilic Interactions , Imidazoles/administration & dosage , Imidazoles/adverse effects , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Liposomes , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Nude , Particle Size , Phenanthrenes/administration & dosage , Phenanthrenes/adverse effects , Phenanthrenes/pharmacokinetics , Phenanthrenes/therapeutic use , Phosphatidylcholines/chemistry , Polyethylene Glycols/chemistry , Solubility , Tissue DistributionABSTRACT
ML-133 is a novel small molecule with potent antiproliferative activity, as shown in cancer cell lines and in a human colon tumor xenograft model. ML-133 reduces the concentration of intracellular labile zinc in HT-29 colon cancer cells, leading to induction of the Krüppel-like factor 4 transcription factor. Krüppel-like factor 4 displaces the positive regulator SP1 from the cyclin D1 promoter, thereby negatively regulating the expression of cyclin D1 and promoting the G(1)-S phase arrest of cell proliferation. The antiproliferative and antitumor activity of ML-133 described in the present study suggests modulation of intracellular zinc homeostasis as a potential strategy for the treatment of several cancer types, and ML-133 represents a promising new class of antitumor agents that deserves further development.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Division/drug effects , Homeostasis/drug effects , Imidazoles/pharmacology , Phenanthrolines/pharmacology , Zinc/metabolism , Base Sequence , Blotting, Western , Cell Cycle , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cyclin D1/genetics , DNA Primers , Electrophoresis, Polyacrylamide Gel , Flow Cytometry , HT29 Cells , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/biosynthesis , Polymerase Chain Reaction , Promoter Regions, Genetic , Sp1 Transcription Factor/metabolism , Up-Regulation/drug effectsABSTRACT
Epidemic Canadian methicillin-resistant Staphylococcus aureus strain 1 (CMRSA-1) comprises related subtypes that differ in phenotype and prevalence, with subtypes 1A, 1B, and 1D representing 1%, 71%, and 18%, respectively, of total CMRSA-1 isolates. The predominant CMRSA-1B subtype possesses a variant of the staphylococcal cassette chromosome mec, harboring pls, which encodes plasmin-sensitive surface protein (Pls). CMRSA-1B cells that express Pls exhibited poor adhesion to keratinocyte extracellular matrix. However, CMRSA-1B and purified Pls adhered to cellular lipids and glycolipids, and Pls promoted bacterial cell-cell interactions. Although exoprotein expression was restricted to a precursor form of lipase in CMRSA-1B, it was not attenuated in virulence relative to CMRSA-1A, which exhibits normal exoprotein expression. In contrast, CMRSA-1D exhibited a pleiotropic defect in exoprotein expression and attenuated virulence relative to CMRSA-1A. These data indicate that the high transmissibility of CMRSA-1B was not achieved at the expense of attenuated virulence and that Pls confers a novel adhesion mechanism.