Semisynthesis of antitumoral acetogenins: SAR of functionalized alkyl-chain bis-tetrahydrofuranic acetogenins, specific inhibitors of mitochondrial complex I

The acetogenins of Annonaceae are known by their potent cytotoxic activity. In fact, they are promising candidates as a new future generation of antit umoral drugs to fight against the current chemiotherapic resistant tumors. The main target enzyme of these compounds is complex I (NADH:ubiquinone oxi doreductase) of the mitochondrial respiratory chain, a key enzymatic comple x of energy metabolism. In an attempt to characterize the relevant structur al factor of the acetogenins that determines the inhibitory potency against this enzyme, we have prepared a series of bis-tetrahydrofuranic acetogenin s with different functional groups along the alkyl chain. They comprise sev eral ore, hydroxylimino, mesylated, triazido, and acetylated derivatives fr om the head series compounds rolliniastatin-1, guanacone, and squamocin. Ou r results suggest a double binding point of acetogenins to the enzyme invol ving the alpha,alpha'-dihydroxylated tetrahydrofuranic system as well as th e alkyl chain that links the terminal alpha,beta -unsaturated-gamma -methyl -gamma -lactone. The former mimics and competes with the ubiquinone substra te. The latter modulates the inhibitory potency following a complex outline in which multiple structural factors probably contribute to an appropriate conformation of the compound to penetrate inside complex I.