Resveratrol-based benzoselenophenes with an enhanced antioxidant and chain breaking capacity

Abstract

The structural modification of the resveratrol scaffold is currently an active issue in the quest for more potent and versatile antioxidant derivatives for biomedical applications. Disclosed herein is an expedient and efficient entry to a novel class of resveratrol derivatives featuring an unprecedented 2-phenylbenzoselenophene skeleton. The new compounds were obtained in good yields by direct selenenylation of resveratrol with Se(0) and SO 2 Cl 2 in dry THF. Varying the [Se : SO 2 Cl 2 : resveratrol] ratio resulted in the formation of the parent benzoselenophene (1) and/or mono (2) and/or dichloro (3) benzoselenophene derivatives. All the benzoselenophene derivatives proved to be more efficient than resveratrol in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assays, with 1 showing an activity nearly comparable to that of Trolox. 1-3 also proved to be more efficient inhibitors than the parent resveratrol in kinetic experiments of styrene autoxidation. DFT calculations of the O-H bond dissociation enthalpy (BDE) revealed that the introduction of the Se-atom causes a significant decrease of the BDE of 3-OH and 5-OH, with just a small increase of the 4'-OH BDE. Compounds 1-3 showed no cytotoxicity at 5 μM concentrations on human keratinocyte (HaCaT) and intestinal (CaCo-2) cell lines.

Natural‐Antioxidant‐Inspired Benzo[b]selenophenes: Synthesis, Redox Properties, and Antiproliferative Activity

“…The cyclization reactions proceeded very smoothly,e ven on am ultigram scale (up to 20 g), and the desired benzo[b]selenophenes (7-9)w ere obtained in 83-95 %y ields. The corresponding 2-unsubstitutedd erivatives (10)(11)(12)w ere successfully obtained from ah igh-yielding deacetonation step (Scheme 2c). We previously reported [6a,7] that 3-bromo-6-fluorobenzo[b]selenophene (10)i saversatile substrate for the preparation of more-complex target compounds, throught he insertion of alkoxys ubstituents at the 6-position by nucleophilic substitution of the fluorine atom and arylationa tt he 3-position through aS uzukic oupling reaction.…”

“…Notably,c ompound 38 was synthesized by the directc yclization of resveratrol on treatment with selenium(II) chloride. [11] However,t his was not ag eneral approach,b ecause, in this case, the substrate underwent regioselective electrophilics ubstitution on the aromatic ring, presumably as the first step of the cyclization process. Furthermore, the product was obtained as am ixture with the chlorinated adduct.…”

Chain‐Breaking Phenolic 2,3‐Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies

“…In resveratrol-derived polyphenolic benzo[b]selenophene antioxidant 5,t he heteroatom caused ac onsiderable weakening of the OÀHb ond in both positions 5a nd 7. [14] As compared to the parent, af ive-fold increase in reactivity was observed (k inh = 8.8 10 5 m À1 s À1 ). Likewise, the close arrangement of Se and OH in ebselenol 6 imposesachain-breaking activity on this compound in addition to its glutathione peroxidase (GPx)like activity.…”

“…In resveratrol‐derived polyphenolic benzo[ b ]selenophene antioxidant 5 , the heteroatom caused a considerable weakening of the O−H bond in both positions 5 and 7 . As compared to the parent, a five‐fold increase in reactivity was observed ( k inh =8.8×10 5 m −1 s −1 ).…”

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

“…For instance, the 1,2,4‐oxadiazole derivative 30 depicted in Figure exhibited higher antioxidant and anti‐inflammatory activities than resveratrol, being able to prevent the interaction of nuclear factor кB (NF‐кB) with DNA through the formation of a hydrogen bond and cation–π interactions between the central ring and Arg56 of p50, a DNA‐binding residue . Moreover, while compound 31 exhibited enhanced antioxidant activity attributable to selenium‐induced reduction of O–H bond dissociation of hydroxy groups in positions 3 and 5, analogue 32 displayed higher anti‐inflammatory activity but lower scavenging capacity due to the presence of the central triple bond . Another analogue, compound 33 , resulted from the combination of pterostilbene ( 13 ) and the pharmacophore moiety of clioquinol, a well‐known metal chelator that improved cognition in patients with AD in a phase II clinical trial .…”