Resveratrol (3,5,4′-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.

Resveratrol (4,3′,5′-trihydroxystilbene) is a naturally occurring antioxidant that inhibits cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and the transcription factor NF-κB. A 78-membered library of resveratrol analogues in which the substituents on the two aryl rings and alkene were varied was synthesized using a solid-phase Wittig olefination reaction. The library contains inhibitors against all three proteins that were more potent than resveratrol itself. Preliminary structure–activity relationships were also obtained from these data that permitted the derivation of pharmacophore models for each of the three targets.

All 4 diastereomeric possibilities for the 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda) residue, found in the cyclic depsipeptide natural products papuamides A–D and mirabamides A–D, were stereoselectively synthesized using a Z-selective Wittig reaction of both enantiomers of 2,4-dimethylhex-2-enyl-triphenylphosphonium bromide with all four diastereoisomers of ethyl-3-formyl-2-methyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate. To elucidate the configuration of Dhtda, the 1H and 13C NMR spectra of the synthetic isomers were compared to those of the natural residue. On the basis of that comparison, it is suggested that the likely configuration of the diastereomer present in Dhtda residue is either (2R,3S,8S) or (2S,3R,8S) in the papuamides and mirabimides.Ethyl (2E,4S)-2,4-dimethyl-2-hexenoateC10H18O2Ee = 100%[α]D25=+20.0 (c 1.7, CHCl3)source of chirality: (S)-2-butan-1-olAbsolute configuration: (S)(2E,4S)-2,4-Dimethyl-2-hexen-1-olC8H16OEe = 100%[α]D25=+22.5 (c 1.3, CHCl3)source of chirality: (S)-2-butan-1-olAbsolute configuration: (S)(2E,4S)-2,4-Dimethyl-2-hexenyltriphenylphosphonium bromideC32H30BrPEe = 100%[α]D25=+12.4 (c 0.5, CHCl3)source of chirality: (S)-2-butan-1-olAbsolute configuration: (S)Diethyl (2R,3R)-1,4-dioxaspiro[4,4]nonane-2,3-dicarboxylateC13H20O6Ee = 100%[α]D25=-32.5 (c 3.4, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3R)Diethyl (2R,3R)-2-methyl-1,4-dioxaspiro[4,4]nonane-2,3-dicarboxylateC14H22O6Ee = 100%[α]D25=-56.1 (c 1.75, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3R)Diethyl (2R,3S)-2-methyl-1,4-dioxaspiro[4,4]nonane-2,3-dicarboxylateC14H22O6Ee = 100%[α]D25=-24.4 (c 0.7, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3S)Ethyl (2R,3S)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylateC20H32O4Ee = 100%[α]D25=+15.9 (c 1.1, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3S,5′S)Ethyl (2R,3R)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylateC20H32O4Ee = 100%[α]D25=+18.9 (c 1.0, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3R,5′S)Ethyl (2S,3R)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylateC20H32O4Ee = 100%[α]D25=+28.0 (c 1.1, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3R,5′S)Ethyl (2S,3S)-3-[(1Z,3E,5S)-3,5-dimethylhepta-1,3-dienyl]-2-methyl-1,4-dioxaspiro[4.4]nonane-2-carboxylateC20H32O4Ee = 100%[α]D25=+13.7 (c 1.1, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3S,5′S)Ethyl (2R,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienylcarboxylateC15H26O4Ee = 100%[α]D25=-80.1 (c 1.0, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3S,8S)Ethyl (2R,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienylcarboxylateC15H26O4Ee = 100%[α]D25=+44.7 (c 1.1, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3R,8S)Ethyl (2S,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienylcarboxylateC15H26O4Ee = 100%[α]D25=+110.4 (c 1.0, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3R,8S)Ethyl (2S,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienylcarboxylateC15H26O4Ee = 100%[α]D25=+3.4 (c 1.25, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3S,8S)Methyl N-[(2R,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienoyl]glycinateC16H27NO5Ee = 100%[α]D25=-16.8 (c 2.5, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3S,8S)Methyl N-[(2R,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienoyl]glycinateC16H27NO5Ee = 100%[α]D25=+38.5 (c 3.75, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2R,3R,8S)Methyl N-[(2S,3R,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienoyl]glycinateC16H27NO5Ee = 100%[α]D25=+55.0 (c 1.0, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3R,8S)Methyl N-[(2S,3S,4Z,6E,8S)-2,3-dihydroxy-2,6,8-trimethyldeca-4,6-dienoyl]glycinateC16H27NO5Ee = 100%[α]D25=-3.2 (c 2.5, CHCl3)source of chirality: (+)-diethyl-l-tartrateAbsolute configuration: (2S,3S,8S)