Biakamides A-D, Unique Polyketides from a Marine Sponge, Act as Selective Growth Inhibitors of Tumor Cells Adapted to Nutrient Starvation
Kotoku, N; Ishida, R; Matsumoto, H; Arai, M; Toda, K; Setiawan, A; Muraoka, O; Kobayashi, M
Biakamides A-D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (Petrosaspongia sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two N-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A-D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A-D showed selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain. © 2017 American Chemical Society.
Bioassay; Chemical analysis; Electron transport properties; Stereochemistry; Anti-proliferative activities; Asymmetric total synthesis; Concentration-dependent manners; Mitochondrial electron transport chain; Nutrient-starvation; One-and two-dimensional NMR; Pancreatic cancers; Primary mode of actions; Nuclear magnetic resonance spectroscopy; 2,4 dimethylpentane 1,5 diol; 5 [(tert butyldiphenylsilyl)oxy] 2,4 dimethylpentan 1 ol; 6 (1,3 dithian 2 yl) 2,4 dimethylhexyl]oxy](tert butyl) diphenylsilane; 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethylheptanal; 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethylheptanoate; 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethylheptanoic acid; 8 [2 [3 [(tert butoxycarbonyl)(methyl)amino]propyl] 1,3 dithian 2 yl] 2,4,6 trimethyloct 2 enoic acid; antineoplastic agent; biakamide A; biakamide B; biakamide C; biakamide D; ethyl 8 [2 [3 [(tert butoxycarbonyl)(methyl)amino]propyl] 1,3 dithian 2 yl] 2,4,6 trimethyloct 2 enoate; methyl 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethyl hept 2 enoate; methyl 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethylhept 2 enoate; methyl 7 [(tert butyldiphenylsilyl)oxy] 4,6 dimethylheptanoate; natural product; polyketide; tert butyl methyl (7,9,11 trimethyl 12 [methyl(thiazol 2 ylmethyl)amino] 4,12 dioxododec 10 en 1 yl]carbamate; tert butyl methyl [3 [2 [3,5,7 trimethyl 8 [methyl (thiazol 2 ylmethyl)amino] 8 oxooct 6 en 1 yl] 1,3 dithian 2 yl] propyl]carbamate; tert butyl [3 [2 (3,5 dimethyl 6 oxohexyl) 1,3 dithian 2yl]propyl](methy)carbamate; tert butyl [3 [2 (6 hydroxy 3,5 dimethylhexyl) 1,3 dithian 2 yl]propyl](methyl)carbamate; tert butyl [4 (chloromethylene) 7,9,11 trimethyl 12 [methyl(thiazol 2 ylmethyl)amino] 12 oxododec 10 en 1 yl] (methyl)carbamate; thiazole; unclassified drug; [[6 (1,3 dithian 2 yl) 2,4 dimethylhexyl]oxy](tert butyl)diphenylsilane; antineoplastic agent; polyketide; acylation; antiproliferative activity; Article; chemical structure; controlled study; drug isolation; drug mechanism; drug synthesis; human; human cell; in vitro study; pancreatic cancer cell line; respiratory chain; signal transduction; sponge (Porifera); stereoisomerism; animal; cell proliferation; chemistry; conformation; dose response; drug effect; drug screening; pancreas tumor; pathology; sponge (Porifera); starvation; structure activity relation; synthesis; tumor cell culture; Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Pancreatic Neoplasms; Polyketides; Porifera; Starvation; Structure-Activity Relationship; Tumor Cells, Cultured