title: Synthesis of Resveratrol Derivatives and In Vitro Screening for Potential Cancer Chemopreventive Activities.
abstract: 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.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, Milano, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Orsini
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, Milano, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Verotta
authors.affiliation: Division Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klimo
authors.affiliation: Division Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Gerhäuser
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001681:Biological Assay; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000614892:3,4',5-tri-O-pivaloyl resveratrol oxide; D000893:Anti-Inflammatory Agents; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D020847:Estrogen Receptor Modulators; D010421:Pentanoic Acids; D013267:Stilbenes; D000077185:Resveratrol
keywords: Aromatase; COX-1; Chemoprevention; Drug metabolism; Nrf2; ORAC; Resveratrol; iNOS