Toward Resolving the Resveratrol Conundrum: Synthesis and in Vivo Pharmacokinetic Evaluation of BCP-Resveratrol

Abstract

Over the last few decades, resveratrol has gained significance due to its impressive array of biological activities; however, its true potential as a drug has been severely constrained by its poor bioavailability. Indeed, several studies have implicated this bioavailability trait as a major road-block to resveratrol's potential clinical applications. To mitigate this pharmacokinetic issue, we envisioned a tactical bioisosteric modification of resveratrol to bicyclo[1.1.1]pentane (BCP) resveratrol. Relying on the beneficial bioisosteric potential demonstrated by the BCP-scaffold, we hypothesized that BCP-resveratrol would have an inherently better in vivo PK profile as compared to its natural counterpart. To validate such a hypothesis, it was necessary to secure a synthetic access to this novel structure. Herein we describe the first synthesis of BCP-resveratrol and disclose its PK properties.

Keywords: BCP; Bioisostere; bicyclo[1.1.1]pentane; pharmacokinetic studies; resveratrol.

Figure 1

Resveratrol (1) and BCP–resveratrol (2).

Scheme 1. Retrosynthetic Analysis of 2

Scheme 2. Hydrolysis Attempts on 6 and 10

Reagents and conditions: (i) 1:1 1 N NaOH/EtOH, rt, 1 h.

Scheme 3. Synthesis of 13

Reagents and conditions: (i) 70% t-BuOOH in water, EDCI, cat. DMAP, DCM, rt, 1 h, 89%; (ii) μW, O₂, pyrazine, 125 °C, 5 h, 52%; (iii) 1.5 M MeLi·LiBr in ether, 0 °C to rt, 3 h, 61%. EDCI = 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide,; DMAP = 4-dimethylaminopyridine.

Scheme 4. Synthesis of the Key Intermediate 18

Reactions and conditions: (i) oxalyl chloride, cat. DMF, DCM, rt, 1 h; (ii) NaBH₄, MeCN, rt, 16 h, 97% (two steps); (iii) TBSCl, imidazole, DCM, rt, 2 h, 89%; (iv) NaOH, MeOH, 60 °C, 1 h, 81%; (v) CH₃NHOCH₃ HC1, EDCI, cat. HOBt, DIPEA, DCM, rt, 16 h; (vi) 3 M PhMgBr in THF, THF, 0 °C to rt; 66% (two steps); (vii) m-CPBA (77%), DCM, 50 °C, 27 h, 85%; (viii) 1 M TBAF in THF, THF, rt, 2 h, 92%; (ix) Dess–Martin periodinane, rt, 1 h, 84%. EDCI = l-ethyl-3-(3-ctimemylammopropyl)carboriliirnide; HOBt = 1-hydroxybenzotriazole; DIPEA = N,N-diisopropylethylamine.

Scheme 5. Completion of the Synthesis of 2

Reactions and conditions: (i) lithium 5-((triphenyl-l⁵-phosphanylidene)methyl)benzene-l,3-bis(olate), THF, −78 to 0 °C, 1.5 h, 31%; (ii) MeLi·LiBr in ether, THF, 0 °C to rt, 1.5 h, 80%.

Figure 2

Comparison of plasma levels of BCP–resveratrol with reported plasma levels of resveratrol during a 1 h time frame.

Figure 3

Formation of glucuronide and sulfate conjugates of resveratrol and BCP–resveratrol in human hepatocytes.

Scheme 6. Synthesis of (±) BCP–Tyrosine Ethyl Ester (23)

Reactions and conditions: (i) ethyl 2-(diethoxyphosphoryl)acetate, 60% NaH, THF, 0 °C to rt, 2 h, 87%; (ii) di-tert-butyl (E)-diazene-l,2-dicarboxylate, Mn(dpm)₃, PhSiH₃, IPA, 0 °C to rt, 2 h, 71%; (iii) TFA, DCM, 0 °C to rt, 16 h; (iv) 0.1 M SmI₂ in THF, 0 °C to rt, 6 h, 45% (2 steps); (v) 37% HC1, EtOH, 80 °C, 48 h, 64%. dpm = 2,2,6,6-tetramethyl-3,5-heptanedionato; IPA = isopropyl alcohol.