New Insights into the French Paradox: Free Radical Scavenging by Resveratrol Yields Cardiovascular Protective Metabolites

Resveratrol was subjected to a diversity-oriented synthesis
using
oxidative transformations by various biorelevant, biomimetic, or biomimetic-related
chemical reagents. Using a combined strategy of ultrahigh-resolution
profiling, bioactivity screening, and bioactivity-guided isolation,
19 metabolites were obtained. The compounds were tested for their in vitro enzyme inhibitory activity on angiotensin-1 converting
enzyme (ACE), cyclooxygenase-1 and -2, and 15-lipoxygenase (LOX),
and evaluated for their relevant drug-like properties in silico. The compounds demonstrated a generally increased cardiovascular
protective and anti-inflammatory potential and better drug-likeness
compared to resveratrol. Trans-δ-viniferin
(6) was identified as a competitive, C-domain-selective
ACE inhibitor that is over 20 times more potent than resveratrol.
Further, trans-ε-viniferin (2)
acted as an over 40 times stronger LOX inhibitor than resveratrol.
While our results cannot be directly translated to the health benefits
of dietary resveratrol consumption without further studies, it is
demonstrated that biologically relevant oxidative environments transform
resveratrol into potent cardiovascular protective and anti-inflammatory
metabolites.