Otto-Diels-Institute of Organic Chemistry, Christian-Albrechts-University of Kiel, 24098 Kiel, Germany.
Institute of Pharmacy, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
J Am Chem Soc. 2022 Aug 24;144(33):15059-15071. doi: 10.1021/jacs.2c03649. Epub 2022 Aug 11.
Photopharmacology is an emerging approach in drug design and pharmacological therapy. Light is used to switch a pharmacophore between a biologically inactive and an active isomer with high spatiotemporal resolution at the site of illness, thus potentially avoiding side effects in neighboring healthy tissue. The most frequently used strategy to design a photoswitchable drug is to replace a suitable functional group in a known bioactive molecule with azobenzene. Our strategy is different in that the photoswitch moiety is closer to the drug's scaffold. Docking studies reveal a very high structural similarity of natural 17β-estradiol and the isomers of dihydroxy diazocines, but not their isomers, respectively. Seven dihydroxy diazocines were synthesized and subjected to a biological estrogen reporter gene assay. Four derivatives exhibit distinct estrogenic activity after irradiation with violet light, which can be shut off with green light. Most remarkably, the photogenerated, active form of one of the active compounds isomerizes back to the inactive form with a half-life of merely several milliseconds in water, but nevertheless is active for more than 3 h in the presence of the estrogen receptor. The results suggest a significant local impact of the ligand-receptor complex toward back-isomerization. Thus, drugs that are active when bound but lose their activity immediately after leaving the receptor could be of great pharmacological value because they strongly increase target specificity. Moreover, the drugs are released into the environment in their inactive form. The latter argument is particularly important for drugs that act as endocrine disruptors.
光药理学是药物设计和药理学治疗中的一种新兴方法。用光将药效团在生物上无活性和活性异构体之间切换，具有高时空分辨率，从而在患病部位潜在地避免邻近健康组织的副作用。设计光可切换药物最常用的策略是用偶氮苯取代已知生物活性分子中的合适功能团。我们的策略不同之处在于，光开关部分更接近药物的支架。对接研究表明，天然 17β-雌二醇及其二羟二氮杂环丁烷的顺式异构体非常相似，但它们的反式异构体则不然。合成了七个二羟二氮杂环丁烷，并进行了生物雌激素报告基因检测。四种衍生物在紫光照射后表现出明显的雌激素活性，绿光照射可关闭其活性。最显著的是，在水中，一种活性化合物的光生成的活性形式在数毫秒内即可异构化为非活性形式，但在雌激素受体存在下仍具有超过 3 小时的活性。结果表明配体-受体复合物对反向异构化有显著的局部影响。因此，当与受体结合时具有活性但在离开受体后立即失去活性的药物可能具有重要的药理学价值，因为它们大大增加了靶标特异性。此外，药物以非活性形式释放到环境中。对于作为内分泌干扰物的药物，后一个论点尤为重要。
