Isolation, biological activity evaluation, structure elucidation, and total synthesis of eliamid: a novel complex I inhibitor.
Eliamid is a secondary metabolite isolated from two bacterial strains. This molecule features a linear polyketide backbone terminated by a tetramic acid amide moiety. Among other biological activities, eliamid shows a high and specific cytostatic action on human lymphoma and cervix carcinoma cell lines. The 2,4-anti relative configuration of the C-2,C-4-dimethyl substituted amide fragment was assigned by means of Breit's rule. The absolute configuration of all stereocenters was determined by a combination of degradation methods, structural similarity analysis and total synthesis. The stereogenic centers were introduced by vinylogous Mukaiyama aldol reaction and two consecutive Myers alkylations. The use of pentafluorophenyl ester as acylation agent allowed the efficient formation of tetramic acid amide. The longest linear sequence in the synthesis consist of 13 steps and proceeds with 12% overall yield. Differential spectroscopy experiments with beef heart submitochondrial particles established that eliamid is a potent inhibitor of the NADH-ubiquinone oxidoreductase complex. Additionally, biosynthesis of eliamid was investigated by feeding experiments with (13)C-labeled precursors.
Helmholtz-Zentrum für Infektionsforschung, Inhoffenstr. 7, Braunschweig, Germany.
Gerhard
G
Höfle
Klaus
K
Gerth
Hans
H
Reichenbach
Brigitte
B
Kunze
Florenz
F
Sasse
Edgar
E
Forche
Evgeny V
EV
Prusov
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009231:Myxococcales / Q000737:chemistry*; D009243:NAD / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011760:Pyrrolidinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D054697:Cytostatic Agents; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; C577029:eliamid; D009243:NAD; D042967:Electron Transport Complex I