Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors.
Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities. Also measured were the abilities of several of the analogues to inhibit respiration as judged by a shift to glycolysis, and to inhibit the growth of several mammalian cell lines. The nature of the pyrone ring was shown to be important to potency of inhibition, as was the length and nature of substituents in the side chain of the analogues.
Leiris
Simon J
SJ
Center for BioEnergetics, The Biodesign Institute, and Department of Chemistry, Arizona State University, Tempe, AZ 85287, USA.
Khdour
Omar M
OM
Segerman
Zachary J
ZJ
Tsosie
Krystal S
KS
Chapuis
Jean-Charles
JC
Hecht
Sidney M
SM
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000475:Alkenes; D011753:Pyrones; C517116:verticipyrone
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