acetogenins and quinone

NADH-quinone oxidoreductase (respiratory complex I) is a key player in mitochondrial energy metabolism. The enzyme couples electron transfer from NADH to quinone with the translocation of protons across the membrane, providing a major proton-motive force that drives ATP synthesis. Recently, X-ray crystallography and cryo-electron microscopy provided further insights into the structure and functions of the enzyme. However, little is known about the mechanism of quinone reduction, which is a crucial step in the energy coupling process. A variety of complex I inhibitors targeting the quinone-binding site have been indispensable tools for mechanistic studies on the enzyme. Using biorationally designed inhibitor probes, the author has accumulated a large amount of experimental data characterizing the actions of complex I inhibitors. On the basis of comprehensive interpretations of the data, the author reviews the structural features of the binding pocket of quinone/inhibitors in bovine mitochondrial complex I.. ATP: adenosine triphosphate; BODIPY: boron dipyrromethene; complex I: proton-translocating NADH-quinone oxidoreductase; DIBO: dibenzocyclooctyne; EM: electron microscopy; FeS: iron-sulfur; FMN: flavin adenine mononucleotide; LDT: ligand-directed tosylate; NADH: nicotinamide adenine dinucleotide; ROS: reactive oxygen species; SMP: submitochondrial particle; TAMRA: 6-carboxy-

Topics: Acetogenins; Amiloride; Animals; Benzoates; Benzoquinones; Binding Sites; Cattle; Electron Transport; Electron Transport Complex I; Humans; Mitochondria; Oxidative Phosphorylation; Pyrazoles; Quinazolines; Reactive Oxygen Species

A small library of analogues of annonaceous acetogenins through click linkage with aromatic moieties is established using a convergent modular fragment-assembly approach. These analogues exhibited low micromolar inhibitory activities against the proliferation of several human cancer cell lines. Structure-activity relationship (SAR) of these analogues indicates that replacement of the methoxy groups of ubiquinone ring with methyl groups is proved to be a useful strategy for improving the anticancer activity of quinone-acetogenin hybrids.

Topics: Acetogenins; Antineoplastic Agents; Benzoquinones; Cell Proliferation; Cell Survival; Click Chemistry; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Hydrocarbons, Aromatic; Molecular Mimicry; Molecular Structure; Small Molecule Libraries; Structure-Activity Relationship; Tumor Cells, Cultured

A new series of linear dimeric compounds mimicking naturally occurring annonaceous acetogenins have been synthesized by bivalent analogue design, and their cytotoxicities have been evaluated against the growth of cancer cells by MTT method. Most of these compounds show selective action favored to human cancer cell lines over normal cell lines, and compound 9 with bis-terminal benzoquinone functionality exhibits an IC(50)=0.40 μM against MCF7 cell lines. This work mentions that appropriate conformational constraints might be a useful optimizing tool for this unique class of anticancer compounds.

Topics: Acetogenins; Antineoplastic Agents; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; Female; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasms