Therapeutic Versatility of Resveratrol Derivatives

nutrients Review Therapeutic Versatility of Resveratrol Derivatives Waqas Nawaz 1, Zhongqin Zhou 2, Sa Deng 1, Xiaodong Ma 1, Xiaochi Ma 1, Chuangang Li 3,* and Xiaohong Shu 1,2,* ID 1 College of Pharmacy, Dalian Medical University, Dalian 116044, China; [email protected] (W.N.); [email protected] (S.D.); [email protected] (X.M.); [email protected] (X.M.) 2 Academy of Integrative Medicine, Dalian Medical University, Dalian 116044, China; [email protected] 3 The Second Affiliated Hospital, Dalian Medical University, Dalian 116023, China * Correspondence: [email protected] (C.L.); [email protected] (X.S.); Tel.: +86-411-8611-0419 (C.L. & X.S.) Received: 15 August 2017; Accepted: 25 October 2017; Published: 29 October 2017 Abstract: Resveratrol, a natural phytoalexin, exhibits a remarkable range of biological activities, such as anticancer, cardioprotective, neuroprotective and antioxidant properties. However, the therapeutic application of resveratrol was encumbered for its low bioavailability. Therefore, many researchers focused on designing and synthesizing the derivatives of resveratrol to enhance the bioavailability and the pharmacological activity of resveratrol. During the past decades, a large number of natural and synthetic resveratrol derivatives were extensively studied, and the methoxylated, hydroxylated and halogenated derivatives of resveratrol received particular more attention for their beneficial bioactivity. So, in this review, we will summarize the chemical structure and the therapeutic versatility of resveratrol derivatives, and thus provide the related structure activity relationship reference for their practical applications. Keywords: resveratrol; resveratrol derivatives; pharmacological activity; structure-activity relationship 1. Introduction Resveratrol (3,5,40-trihydroxystilbene) is a natural phytoalexin produced by numerous plants in response to ultraviolet radiation, injury, fungal or bacterial infection. Resveratrol was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940 [1,2], and is well known for its “French Paradox” [2]. However, resveratrol not only exists in red wine but is present in natural foods including grape, blueberry, raspberry and mulberry, and the exact concentration of resveratrol in each source varies widely [3]. In the last few decades, stilbene-based compounds are widely investigated due to their diverse range of biological activities [4]. The chemical structure of resveratrol is composed of two aromatic rings allied by a methylene bridge, and presents in both trans- and cis-isomeric forms naturally (Figure1), however, the majority of the recorded medical advantages are attributed to trans-resveratrol but not its cis-form, so the structure activity relationship is the key point to determine the biological activities of resveratrol [5,6]. A large number of preclinical studies have proved that resveratrol could impact a variety of human pathophysiological conditions [7]. The latest search (on 19 June 2017) from the database of the new ClinicalTrials.gov (http://clinicaltrials.gov/) shows that there are 104 clinical trials (statuses including active, recruiting, enrolling by invitation and completed) involving in resveratrol, and these trials aim to investigate the pharmacological activity of resveratrol in treating cancer, diabetes, obesity, and other cardiovascular and neurodegenerative diseases. The safety and tolerability of resveratrol as a medicinal product are investigated in the clinical trials [8,9]. It is extremely encouraged that doses of resveratrol of up to 5 g/day, taken for a month, are safe and well tolerated [9,10]. In humans, resveratrol Nutrients 2017, 9, 1188; doi:10.3390/nu9111188 www.mdpi.com/journal/nutrients NutrientsNutrients2017, 9 2017, 1188, 9, 1188 2 of 27 26 [9,10]. In humans, resveratrol could be absorbed after oral administration, but the plasma could be absorbed after oral administration, but the plasma concentration and tissue distribution concentration and tissue distribution are low for its rapid and extensive phase II metabolism [10–13]. are lowSo, for the its search rapid andfor a extensive method phasehow to II metabolismincrease the [bioavailability10–13]. So, the of search resveratrol for a method receives how more to increaseattention. the bioavailability of resveratrol receives more attention. HO OH OH HO HO OH A B Figure 1. Chemical structures of trans-resveratrol (3,5,40-trihydroxystilbene) and its cis-isomer. Figure 1. Chemical structures of trans‐resveratrol (3,5,4′‐trihydroxystilbene) and its cis‐isomer. (A) (A) trans-resveratrol; (B) cis-resveratrol. trans‐resveratrol; (B) cis‐resveratrol. ResveratrolResveratrol is a smallis a small molecule molecule with with a molecular a molecular weight weight of of 228.247 228.247 g/mol, g/mol, andand itit isis equippedequipped with differentwith different functional functional groups groups including including phenolic phenolic hydroxyl hydroxyl groups, groups, aromatic aromatic rings rings andand aa doubledouble bondbond [14]. [14]. These These functional functional groups groups provideprovide resveratrol with with great great potential potential to be to modified be modified into into activeactive derivativesderivatives withwith more diversifieddiversified therapeutic therapeutic efficacies efficacies [15–17].[15–17 ].InIn the the past past few few years, years, researchersresearchers have have synthesized synthesized a series a series of resveratrolof resveratrol derivatives derivatives and and evaluated evaluated theirtheir biologicalbiological activities.activities.Pan Pan et al. et foundal. found that thattrans trans-3,4‐0,5-trimethoxystilbene3,4′,5‐trimethoxystilbene showed showed higherhigher potencypotency thanthan resveratrolresveratrol in inhibiting in inhibiting angiogenesis, angiogenesis, and and it alsoit also possessed possessed the the potent potent proapoptotic proapoptotic activity [18]. [18]. LocatelliLocatelli et al. etsynthesized al. synthesized 4,40-dihydroxy- 4,4′‐dihydroxytrans‐trans-stilbene,‐stilbene, which which showed showed strongstrong antioxidantantioxidant properties [19]. Das et al. synthesized various monoalkoxy and dialkoxy derivatives of resveratrol to properties [19]. Das et al. synthesized various monoalkoxy and dialkoxy derivatives of resveratrol improve Protein kinase C (PKC) binding activity, which was proved to be more effective than the to improve Protein kinase C (PKC) binding activity, which was proved to be more effective than the parent compound [20]. Many studies showed pterostilbene possess better chemotherapeutic parent compound [20]. Many studies showed pterostilbene possess better chemotherapeutic properties properties than resveratrol via in vitro and in vivo experiments [21]. than resveratrolThe structure via in vitro‐activity and relationship in vivo experiments (SAR) studies [21]. have revealed that the parent structure of Theresveratrol structure-activity is an essential relationship component and (SAR) is vital studies for its have specific revealed therapeutic that effects the parent [15]. Substitution structure of resveratrolof hydroxyl is groups an essential of resveratrol component to methoxy and groups is vital significantly for its specific boosted therapeutic its cytotoxic activity effects [22], [15]. Substitutionand the of hydroxy hydroxyl group groups in the of trans resveratrol conformation to methoxy at the groups4‐ and 4 significantly′‐positions of boostedthe stilbene its cytotoxicstructure 0 activityhas [ 22been], and reported the hydroxy as essential group for the in antiproliferative the trans conformation effect of resveratrol at the 4- and[23]. 4The-positions introduction of the of stilbenehalogen structure groups has could been provide reported the as antibacterial essential for activity the antiproliferative of resveratrol [24]. effect In ofaddition, resveratrol there [ 23are]. The introductionvarious naturally of halogen occurring groups and synthetic could stilbene provide‐like the compounds antibacterial which activity show ofdifferent resveratrol bioactivity [24]. In addition,but are there related are to various their chemical naturally structure. occurring So and the syntheticdesigning stilbene-like and synthesizing compounds of novel which resveratrol show differentderivatives bioactivity have but received are related much to more their of chemical attention structure. from pharmacologists So the designing and andthus synthesizing to enhance the of noveltherapeutic resveratrol derivativesversatility of have resveratrol. received During much morethe last of attentionfew decades, from various pharmacologists natural and and synthetic thus to enhanceresveratrol the therapeutic derivatives versatility were studied, of resveratrol. and the During methoxylated, the last few hydroxylated decades, various and naturalhalogenated and syntheticderivatives resveratrol of resveratrol derivatives were were received studied, andthe special the methoxylated, attention due hydroxylated to their diverse and halogenated therapeutic derivativespotential. of resveratrol This review were aims received to highlight the specialthe role attention of the resveratrol due to their derivatives diverse such therapeutic as methoxylated, potential. hydroxylated and halogenated derivatives, and focus on their therapeutic versatility and their This review aims to highlight the role of the resveratrol derivatives such as methoxylated, hydroxylated action mechanism. and halogenated derivatives,

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