Synthesis of Resveratrol Derivatives and In Vitro Screening for Potential Cancer Chemopreventive Activities

New resveratrol (trans‐3,4’,5‐trihydroxystilbene) analogs were synthesized and screened for their in vitro cancer chemopreventive potential using various bioassays relevant for the prevention of carcinogenesis in humans: two assays to detect modulators of carcinogen metabolism (Cyp1A inhibition; determination of NAD(P)H/quinone reductase (QR) activity), three assays to identify radical scavenging and antioxidant properties (DPPH, ORAC, superoxide anion radicals in differentiated HL‐60 cells), four assays to determine anti‐inflammatory and anti‐hormonal effects (iNOS, Cox‐1 and aromatase inhibition, anti‐estrogenic potential). 3,4′,5‐Tri‐O‐methyl resveratrol 1a was about sevenfold more active than resveratrol in inhibiting Cyp1A activity, it was a potent inducer of QR activity, and it showed pure anti‐estrogenic activity (whereas resveratrol is a known mixed estrogen (ant)agonist with both estrogenic and anti‐estrogenic properties). Dual estrogen ant‐/agonist activity was restored in the mono‐O‐benzyl‐substituted derivatives 4b (4′‐O‐benzyl resveratrol) and 5b (3‐O‐benzyl resveratrol). With respect to aromatase inhibition (Cyp19), which provided the highest number of actives, the benzyl‐substituted series was more potent than the methyl‐substituted derivatives of resveratrol, and 3‐O‐benzyl resveratrol 5b was about eightfold more active than resveratrol. Overall, 3,4′,5‐tri‐O‐pivaloyl resveratrol oxide 7c was identified as a potent inducer of phase 2 enzymes concomitant with inhibition of LPS‐mediated iNOS induction. A variety of resveratrol analogs were synthesized and screened for their in vitro cancer chemopreventive potential using a series of bioassays relevant for the prevention of carcinogenesis in humans. 3,4’,5‐Tri‐O‐pivaloyl resveratrol oxide 7c was identified as a potent inducer of phase 2 enzymes concomitant with inhibition of LPS‐mediated iNOS induction.