ABSTRACT
Novel triazine analogues of 5-alkyl-2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones (F(2)-DABOs), previously described by us as nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs), were tested for their antiproliferative and cytodifferentiating activity on the A-375 human melanoma cell line. Most of the tested derivatives were effective in decreasing cell proliferation, facilitating morphological differentiation, and reprogramming gene expression. All these effects were reversible upon withdrawal of RT inhibitors. Among the compounds tested, 3 f showed the highest antiproliferative effect, whereas compound 6 c, although not affecting cell proliferation, is endowed with a strong cytodifferentiating effect, which is probably related to a marked upregulation of the e-cad gene. These results support the potential of NNRTIs as valuable antitumor agents.
Subject(s)
Triazines/pharmacology , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistryABSTRACT
Two 2,6-difluoro-DABO derivatives (MC 1047, 1, and MC 1220, 2, respectively) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compounds significantly reduced cell proliferation and facilitated the morphological differentiation of cells. These results propose F(2)-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Pyrimidinones/chemical synthesis , RNA-Directed DNA Polymerase/metabolism , Reverse Transcriptase Inhibitors/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Fluorobenzenes , Humans , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel benzyl- and phenyl-isothioureidic derivatives have been synthesised and evaluated as inhibitors of nitric oxide synthesis, induced in lipopolysaccharide (LPS)-activated J774.A1 macrophage cell line. The most potent iNOS inhibitor resulting was 1-methyl-3-phenyl-S-methyl isothiourea 5l.
Subject(s)
Nitric Oxide Synthase/antagonists & inhibitors , Thiourea/chemical synthesis , Thiourea/pharmacology , Animals , Cell Line , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lipopolysaccharides , Macrophages/enzymology , Mice , Nitric Oxide Synthase Type II , Structure-Activity RelationshipABSTRACT
The anti-amoebic power of a series of bis-thioureidic derivatives against amoeba, responsible for a serious form of keratitis of the cornea, has been analysed. The synthesis of these products is also described.
Subject(s)
Acanthamoeba/drug effects , Amebicides/pharmacology , Thiourea/analogs & derivatives , Thiourea/chemistry , Animals , Cornea/parasitology , Humans , In Vitro Techniques , Keratitis/parasitology , Magnetic Resonance Spectroscopy , Parasitic Sensitivity Tests , Structure-Activity Relationship , Thiourea/pharmacologyABSTRACT
Recent developments in biomedical science have shown that free radicals are involved in many diseases. They attack the unsaturated fatty acids in the biomembrane resulting in membrane lipid peroxidation, which is strongly connected to aging, carcinogenesis and atherosclerosis. Free radicals also attack DNA and cause mutation leading to cancer. In addition lipid peroxidation is an important factor of deterioration in the processing and storage of food. Therefore, it is important to search for new effective radical scavengers (Sci. Rev. 2 (1997) 152; J. Nat. Prod. Rev. 63 (2000) 1035). In this manuscript we describe the antioxidant activity of new thioureidic compounds.
