ABSTRACT
Eight dicationic compounds related to pentamidine were studied for trypanocidal activity in seven trypanosome isolates. In vitro studies revealed that diamidines are more potent than diimidazolines. For example, 2 (a diamidine) and 4 (a diimidazoline) inhibited the growth of KETRI 243 with IC50 values of 2.3 and 900 nM, respectively. Introduction of polar groups into the linker decreased the effectiveness of the compounds against drug-resistant trypanosomes. In compounds with a 2-butene linker between the cationic groups, trans-isomers were more potent than cis-isomers. The cis- and trans-buteneamidines cured infection caused by Trypanosoma brucei brucei (EATRO Lab 110) and protected mice against infection by Trypanosoma brucei rhodesiense isolates, some of which are resistant to diamidines and melarsoprol.
Subject(s)
Cations, Divalent/pharmacology , Pentamidine/analogs & derivatives , Pentamidine/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei rhodesiense/drug effects , Trypanosomiasis, African/drug therapy , Animals , Cations, Divalent/chemical synthesis , Cations, Divalent/chemistry , Cations, Divalent/therapeutic use , Cattle , DNA/genetics , DNA/metabolism , Drug Design , Drug Evaluation, Preclinical , Female , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Pentamidine/chemical synthesis , Pentamidine/therapeutic use , Structure-Activity Relationship , Thymus Gland , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanocidal Agents/therapeutic useABSTRACT
A series of oleanolic acid A/B-ring partial analogues was synthesized and tested for their complement inhibitory activity as well as cytotoxic properties. All target compounds and one intermediate exhibited moderate complement inhibitory potency. These compounds also showed cytotoxicity on malignant melanoma cell line, SK-MEL.
Subject(s)
Complement Inactivator Proteins/chemical synthesis , Complement Inactivator Proteins/pharmacology , Oleanolic Acid/chemical synthesis , Oleanolic Acid/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Melanoma/pathology , Oleanolic Acid/chemistry , Stereoisomerism , Tumor Cells, CulturedABSTRACT
A number of semisynthetic analogs of oleanolic acid have been synthesized and tested for their complement inhibitory, cytotoxic and apoptotic activities. Among these, compounds 10 and 17 exhibited complement inhibitory potency superior to oleanolic acid. Both have also shown a moderate improvement in in vitro therapeutic index (T.I.).
Subject(s)
Complement Inactivator Proteins/chemical synthesis , Complement Inactivator Proteins/pharmacology , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Complement Inactivator Proteins/chemistry , DNA Fragmentation , Drug Evaluation, Preclinical , Humans , Melanoma/drug therapy , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
sn-1 Palmitoyl lysophosphatidylinositol is found in carrot suspension culture cells and can be phosphorylated to [32P]lysophosphatidylinositol monophosphate (LPIP) when [gamma 32P]ATP is added to isolated membranes. Based on in vivo labeling studies, [3H]inositol sn-1 palmitoyl LPIP was found predominantly in the plasma membrane-rich fraction or upper phase isolated by aqueous two-phase partitioning and LPI was found in the intracellular membrane-rich fraction or lower phase (Wheeler and Boss, Plant Physiol. 85, 389-392, 1987). While both membrane fractions phosphorylated LPI in vitro, the apparent Km for LPI in the intracellular membrane fraction was 180 microM and for the plasma membrane was 580 microM. When cells were treated with the ionophore, monensin, the percentage of [3H]inositol LPIP increased in the whole cell lipid extract. However, the monensin treatment decreased the amount of [3H]inositol LPIP and PIP recovered in the plasma membrane fraction relative to the sum of the individual lipid, [3H]inositol LPIP or PIP, respectively, recovered in both membrane fractions.
Subject(s)
Lysophospholipids/metabolism , Membranes/metabolism , Phosphorylation , Plants, Edible/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Diglycerides/metabolism , Inositol/metabolism , Intracellular Membranes/drug effects , Intracellular Membranes/metabolism , Lysophospholipids/blood , Membranes/drug effects , Monensin/pharmacology , Phosphatidylinositols/blood , Phosphatidylinositols/metabolism , Phospholipases A/metabolismABSTRACT
The unmediated one-electron reduction and reoxidation of ferric cytochrome c peroxidase at fluoride-doped tin oxide electrodes is reported. A long range interfacial electron transfer distance of 17 A is postulated by analogy to the Poulos/Kraut model for the cytochrome c peroxidase/cytochrome c electron transfer complex. The utility of the interfacial electrochemical approach for investigating cytochrome c peroxidase electron transfer behavior is discussed.
