Quinone-annonaceous acetogenins: synthesis and complex I inhibition studies of a new class of natural product hybrids.
The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiquinone. For both syntheses, a modular, highly convergent approach was applied. Quinone-mucocin was constructed out of a tetrahydropyran (THP) component 1, a tetrahydrofuran (THF) unit 2, and a quinone precursor 3. A stereoselective, organometallic coupling reaction was chosen for the addition of the THP unit to the rest of the molecule. In the final step, the oxidation to the free quinone was achieved by using cerium(IV) ammonium nitrate (CAN) as the oxidizing agent. Quinone-squamocin D was assembled in a similar manner, from the chiral side chain bromide 16, the central bis-THF core 17, and the quinone precursor 18. Inhibition of complex I (isolated from bovine heart mitochondria) by the quinone acetogenins and several smaller building blocks was examined; quinone mucocin and quinone-squamocin D act as strong inhibitors of complex I. These results and the data from the smaller substructures indicate that other substructures of the acetogenins besides the butenolide group, such as the polyether component and the lipophilic left-hand side chain, are necessary for the strong binding of the acetogenins to complex I.
Arndt
S
S
Institut für Chemie, Humboldt-Universität zu Berlin, Germany.
Emde
U
U
Bäurle
S
S
Friedrich
T
T
Grubert
L
L
Koert
U
U
D000818:Animals; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; D011714:Pyrans; D011809:Quinones; C112079:isomurisolenin; C413144:mucocin; C431343:quinone-mucocin; C431344:quinone-squamocin D; C004532:quinone; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I