Semisynthesis of antitumoral acetogenins: SAR of functionalized alkyl-chain bis-tetrahydrofuranic acetogenins, specific inhibitors of mitochondrial complex I
T. Gallardo et al., Semisynthesis of antitumoral acetogenins: SAR of functionalized alkyl-chain bis-tetrahydrofuranic acetogenins, specific inhibitors of mitochondrial complex I, J MED CHEM, 43(25), 2000, pp. 4793-4800
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.