ABSTRACT
We investigated the aluminium-salen complex MBR-8 as a potential anti-cancer agent. To see apoptotic effects induced by MBR-8, alone and in combination with common cytostatic drugs, DNA-fragmentations were studied using the flow cytometric analysis. Western blot analysis and measurement of the mitochondrial membrane potential with a JC-1 dye were employed to identify the pathway of apoptosis. An impressive overcoming of multidrug-resistance in leukemia (Nalm6) cells was observed. Additionally, solid tumor cells including Burkitt-like lymphoma (BJAB) and mamma carcinoma cells (MCF-7) are affected by MBR-8 in the same way. Western blot analysis revealed activation of caspase-3. MBR-8 showed very pronounced selectivity with regard to tumor cells and high synergistic effects in Nalm6 and daunorubicin-resistant Nalm6 cells when administered in combination with vincristine, daunorubicin and doxorubicin. The aluminium-salen complex MBR-8 showed very promising anti-cancer properties which warrant further development towards a cytostatic agent for future chemotherapy. Studies on aluminium compounds for cancer therapy are rare, and our report adds to this important body of knowledge.
Subject(s)
Aluminum/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Coordination Complexes/pharmacology , Cytostatic Agents/pharmacology , Ethylenediamines/pharmacology , Aluminum/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Cytostatic Agents/chemical synthesis , Cytostatic Agents/chemistry , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Ethylenediamines/chemistry , HumansABSTRACT
A very small number of cobalt complexes is examined in oncology research. In this work, we investigate the cobalt (III) salen complex MBR-60 that turns out to be a promising anticancer drug. It induces apoptosis in Nalm6 leukemia and BJAB lymphoma cells and overcomes multidrug resistances by blocking the drug efflux pump P-glycoprotein. It further develops the apoptotic effects over the intrinsic pathway. An activation of caspase-3, caspase-8 and caspase-9 can be detected by western blot analysis. The independence of CD95 is shown by similar apoptotic inductions in BJAB and BJAB FADDdn cells. MBR-60 displays synergistic effects with daunorubicin and vincristine and has a selectivity to tumor cells. In comparison to the apoptotic effects of MBR-60 in BJAB lymphoma cells, the cobalt-free ligand 5 does not influence these cells. The research highlights that a cobalt complex has a therapeutic potential for cancer treating with a focus on drug-resistant tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cobalt/pharmacology , Coordination Complexes/pharmacology , Drug Discovery , Ethylenediamines/pharmacology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cobalt/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Ethylenediamines/chemistry , Humans , Mitochondrial Transmembrane Permeability-Driven Necrosis/drug effects , Molecular Structure , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
This article describes the synthesis of a library of structurally diverse bifunctional organocatalysts bearing both a quasi-Lewis acidic (thio)urea moiety and a Brønsted basic tertiary amine group. Sequential modification of the modular catalyst structure and subsequent screening of the compounds in the alcoholytic dynamic kinetic resolution (DKR) of azlactones revealed valuable structure-activity relationships. In particular, a "hit-structure" was identified which provides e.g.N-benzoyl-tert-leucine allyl ester in an excellent enantiomeric excess of 95%.
Subject(s)
Amines/chemistry , Lactones/chemistry , Thiourea/chemistry , Catalysis , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Diamines/chemistry , Kinetics , Stereoisomerism , Thiourea/analogs & derivativesABSTRACT
New chiral catalyst systems were developed for the reaction of carbon dioxide with propylene oxide (PO) at atmospheric pressure to generate enantiomerically enriched propylene carbonate (PC). The best selectivity was achieved with a Co(III)(salen)-trifluoroacetyl complex and bis(triphenylphosphoranylidene)ammonium fluoride (PPN+F-) as catalysts, affording PC in 40% yield and 83% ee (selectivity factor = 19). In addition, PC was prepared for the first time by kinetic resolution of PO with tetrabutylammonium methyl carbonate (TBAMC, nBu4N+ (-)OOCOMe). With TBAMC as "activated CO2", up to 71% ee was obtained.
