Quinone-Annonaceous Acetogenins: Synthesis and Complex I Inhibition Studies of a New Class of Natural Product Hybrids

Abstract

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.

Natural Product Hybrids as New Leads for Drug Discovery

“…The quinone–mucocin 312 exhibited a K i 50 value of 3.6 n M , about tenfold more active than mucocin ( 310 ) itself. In contrast, quinone–squamocin D 313 was slightly less potent than squamocin A 109b…”

Randomized clinical trial of ultrasonicversuselectrocautery dissection of the gallbladder in laparoscopic cholecystectomy

“…Tabelle 9 zeigt die Ergebnisse zur Komplex‐I‐Inhibition durch die beiden Hybride 312 und 313 . Das Chinon‐Mucocin‐Hybrid 312 war mit einem K i 50 von 3.6 n M etwa zehnmal aktiver als Mucocin ( 310 ) selbst, das Chinon‐Squamocin D‐Hybrid 313 war etwas weniger wirksam als Squamocin A 109b…”

Medicinal Chemistry of Annonaceous Acetogenins: Design, Synthesis, and Biological Evaluation of Novel Analogues

“…To clarify the mode of action of acetogenins, Koert et al . designed quinone-mucocin 166 and quinone-squamocin D 168 in which the γ-lactone moiety was exchanged for the quinone portion of ubiquinone, the natural substrate of complex I ( Scheme 12 ) [ 47 , 48 ]. A representative synthetic pathway is given by the preparation of 166 .…”