Mays Jared R, Weller Roska Rachel L, Sarfaraz Sami, Mukhtar Hasan, Rajski Scott R
University of Wisconsin-Madison, School of Pharmacy, 777 Highland Avenue, Madison, WI 53705-2222, USA.
Chembiochem. 2008 Mar 25;9(5):729-47. doi: 10.1002/cbic.200700586.
Isothiocyanates (ITCs) are one of the many classes of breakdown products of glucosinolates found in crucifers such as broccoli and are thought to be partially responsible for the reduced risk of degenerative diseases associated with the consumption of vegetables. The production of ITCs such as L-sulforaphane is dependent on the hydrolytic bioactivities of myrosinase, localized both within vegetable tissues and within flora of the human GI tract, and is associated with important cancer chemopreventive activities. We hypothesized that novel isothiocyanates with enhanced chemopreventive properties relative to L-sulforaphane could be identified and that their glucosinolate precursors could be synthesized. From a library of 30 synthetic ITCs, we identified several with bioactivities equal or superior to those of L-sulforaphane. The corresponding non-natural glucosinolate precursors to these novel ITCs were constructed and found to be substrates for myrosinase. By utilizing a novel RP-HPLC assay to monitor myrosinase-dependent hydrolysis reactions, 2,2-diphenylethyl glucosinolate and (biphenyl-2-yl)methyl glucosinolate were shown to exhibit 26.5 and 2.8 %, respectively, of the relative activity of sinigrin and produced their corresponding ITCs in varying yields. These data support the notion that non-natural glucosinolates can act as prodrugs for novel ITCs, with a mechanism of action reliant on their hydrolytic cleavage by myrosinase. Such non-natural glucosinolates may serve as very economical chemopreventive agents for individuals at risk for cancers of and around the GI tract.
异硫氰酸盐（ITCs）是十字花科蔬菜（如西兰花）中发现的硫代葡萄糖苷众多分解产物中的一类，被认为与食用蔬菜相关的退行性疾病风险降低有部分关联。诸如L - 萝卜硫素等ITCs的产生取决于黑芥子酶的水解生物活性，黑芥子酶既存在于蔬菜组织中，也存在于人体胃肠道菌群中，并且与重要的癌症化学预防活性相关。我们推测，相对于L - 萝卜硫素，具有增强化学预防特性的新型异硫氰酸盐能够被鉴定出来，并且它们的硫代葡萄糖苷前体能够被合成。从30种合成ITCs的文库中，我们鉴定出了几种生物活性等同于或优于L - 萝卜硫素的化合物。构建了这些新型ITCs相应的非天然硫代葡萄糖苷前体，并发现它们是黑芥子酶的底物。通过利用一种新型反相高效液相色谱法（RP - HPLC）测定法来监测依赖黑芥子酶的水解反应，结果表明，2,2 - 二苯乙基硫代葡萄糖苷和（联苯 - 2 - 基）甲基硫代葡萄糖苷分别表现出芥子硫苷相对活性的26.5%和2.8%，并以不同产率产生了它们相应的ITCs。这些数据支持了这样一种观点，即非天然硫代葡萄糖苷可以作为新型ITCs的前药，其作用机制依赖于它们被黑芥子酶水解裂解。这种非天然硫代葡萄糖苷可能作为非常经济的化学预防剂，用于胃肠道及其周围癌症风险人群。
