Abstract：
Tapinarof (3,5-dihydroxy-4-isopropylstilbene) is a therapeutic agent used in the treatment of psoriasis (VTAMA®). In this study, we examined the redox behaviour, (photo)stability, (photo)toxicity and (bio)transformation of tapinarof in the context of a structure-activity relationship study. Selected derivatives of the structurally related tapinarof were investigated, namely resveratrol, pterostilbene, pinosylvin and its methyl ether. Tapinarof undergoes electrochemical oxidation in a neutral aqueous medium at a potential of around +0.5 V (vs. Ag|AgCl|3M KCl). The anodic reaction of this substance is a proton-dependent irreversible and adsorption-driven process. The pKa value of tapinarof corresponds to 9.19 or 9.93, based on empirical and QM calculation approach, respectively. The oxidation potentials of tapinarof and its analogues correlate well with their HOMO (highest occupied molecular orbital) energy level. The ability to scavenge the DPPH radical decreased in the order trolox ≥ resveratrol > pterostilbene > tapinarof > pinosylvin ≫ pinosylvin methyl ether. It was also confirmed that tapinarof, being a moderate electron donor, is able to scavenge the ABTS radical and inhibit lipid peroxidation. The 4\'-OH group plays a pivotal role in antioxidant action of stilbenols. During the stability studies, it was shown that tapinarof is subject to spontaneous degradation under aqueous conditions, and its degradation is accelerated at elevated temperatures and after exposure to UVA (315-399 nm) radiation. In aqueous media at pH 7.4, we observed an ∼50 % degradation of tapinarof after 48 h at laboratory temperature. The main UVA photodegradation processes include dihydroxylation and hydration. In conclusion, the phototoxic effect of tapinarof on a human keratinocytes cell line (HaCaT) was evaluated. Tapinarof exhibited a clear phototoxic effect, similar to phototoxic standard chlorpromazine. The IC50 values of the cytotoxicity and phototoxic effects of tapinarof correspond to 27.6 and 3.7 μM, respectively. The main HaCaT biotransformation products of tapinarof are sulfates and glucuronides.
摘要：
Tapinarof（3,5-二羟基-4-异丙基二苯乙烯）是用于治疗牛皮癣（VTAMA®）的治疗剂。在这项研究中,我们检查了氧化还原行为，（照片）稳定性，在结构-活性关系研究的背景下，tapinarof的（照片）毒性和（生物）转化。研究了结构相关的tapinarof的选定衍生物，即白藜芦醇，蝶芪,松果素及其甲基醚。Tapinarof在中性水性介质中在约0.5V的电势下进行电化学氧化（与Ag|AgCl|3MKCl)。该物质的阳极反应是质子依赖的不可逆和吸附驱动的过程。根据经验和QM计算方法，tapinarof的pKa值对应于9.19或9.93，分别。tapinarof及其类似物的氧化电位与其HOMO（最高占据分子轨道）能量密切相关。清除DPPH自由基的能力按以下顺序降低：trolox≥白藜芦醇>蝶芪>tapinarof>pinosylvin>>pinosylvin甲基醚。还证实了tapinarof，作为一个适度的电子供体，能够清除ABTS自由基并抑制脂质过氧化。4'-OH基团在醇的抗氧化作用中起关键作用。在稳定性研究中，结果表明，tapinarof在含水条件下自发降解，在高温下和暴露于UVA（315-399nm）辐射后，其降解加速。在pH7.4的水介质中，在实验室温度下48小时后，我们观察到tapinarof降解约50％。主要的UVA光降解过程包括二羟基化和水合。总之,评估了tapinarof对人角质形成细胞系（HaCaT）的光毒性作用。Tapinarof表现出明显的光毒性作用，类似于光毒性标准氯丙嗪。tapinarof的细胞毒性和光毒性效应的IC50值对应于27.6和3.7μM，分别。tapinarof的主要HaCaT生物转化产物是硫酸盐和葡糖苷酸。
