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 s ynthesized. In these hybrids, the butenolide unit of the annonaceous acetog enins mucocin and squamocin D is exchanged for the quinone moiety of the na tural 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 qu inone 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 is. Inhibition of comple x I (isolated from bovine heart mitochondria) by the quinone acetogenins an d several smaller building blocks was examined; quinone-mucocin and quinone -squamocin D act as strong inhibitors of complex I. These results and the d ata 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 bindi ng of the acetogenins to complex I.