Ajoene is an organosulfur compound found in crushed garlic, that exerts its anti‐cancer activity by S‐thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability. In this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (4‐7, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was found that the allyl‐S sulfur of the disulfide was more electrophilic to Sthiolysis based on calculations of the global electrophilicity index (ω); and the condensed electrophilic Fukui function fk+ . S‐Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (10, 12) and deoxydihydroajoenes (9, 11) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.

中文翻译：

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寻找阿霍烯最佳点：控制其血液稳定性和癌症细胞毒性的结构-活性关系

阿霍烯是一种在压碎的大蒜中发现的有机硫化合物，通过对蛋白质上的半胱氨酸残基进行 S-硫醇化来发挥其抗癌活性。由于生物利用度有限，其发展受到阻碍。在这项研究中，我们合成了阿霍烯的类似物，以探讨阿霍烯乙烯基二硫/亚砜核心在细胞毒性和血液稳定性方面的重要性。还引入极性侧基以提高水溶性。研究发现，含有乙烯基二硫官能团（4-7，如阿霍烯）的衍生物与去除双键的类似物相比具有更强的细胞毒性，尽管后者表现出优异的血液稳定性。通过整体亲电指数（ω）的计算，发现二硫化物中的烯丙基-S硫对硫解作用更具亲电性；和浓缩的亲电福井函数 fk+ 。根据去质子化硫醇盐的熵和焓计算，发现 S-硫解作用对于乙烯基二硫化物具有放能作用。衍生化二氢 (10, 12) 和脱氧二氢阿霍烯 (9, 11) 产生的类似物的效力稍差，但血液稳定性大大提高。总的来说，脱氧二氢阿霍烯是进一步治疗开发的良好候选者。