The natural product curcumin is often presented as a source of inspiration in the field of drug development because of its therapeutic diversity and safety for human consumption. However, although curcumin indeed shows an interesting profile in terms of biological activity, its low oral bioavailability, poor stability and unclear mechanism of action considerably weakens its case as a marketable drug. In that context, several modifications to the curcumin structure have previously been realized in our lab, culminating in i.a. benzothiazepane-based derivatives with improved drug-like properties and significant cancer cell cytotoxicity. To further explore their structure-activity relationships and to improve their antitumoral activity, we synthesized a library of new 2-heteroaryl-4-(4-heteroaryl-2-oxobut-3-en-1-ylidene)benzothiazepanes, which were evaluated for cytotoxicity against eight different cancer cell lines. From this screening, pyridine-substituted benzothiazepanes emerged as broad-spectrum anticancer agents, whereas 2-thienyl benzothiazepanes and a side product, formed through a double Michael addition reaction, surfaced as promising structures for further elaboration because of their highly selective activity against the NCI–H460 lung cancer cell line.

中文翻译：

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2-杂芳基-4-(4-杂芳基-2-氧代丁-3-en-1-亚基)-取代的苯并硫氮杂环己烷的合成和癌细胞细胞毒性

天然产物姜黄素因其治疗多样性和人类消费的安全性而经常被视为药物开发领域的灵感来源。然而，尽管姜黄素确实在生物活性方面表现出令人感兴趣的特征，但其口服生物利用度低、稳定性差和作用机制不明确，大大削弱了其作为可销售药物的地位。在这种情况下，我们的实验室之前已经实现了对姜黄素结构的一些修饰，最终产生了基于苯并硫氮杂环庚烷的衍生物，具有改进的药物样特性和显着的癌细胞细胞毒性。为了进一步探索它们的结构-活性关系并提高其抗肿瘤活性，我们合成了一个新的2-杂芳基-4-(4-杂芳基-2-氧代丁-3-en-1-亚基)苯并硫氮杂卓化合物库，并对其进行了评估针对八种不同癌细胞系的细胞毒性。从这次筛选中，吡啶取代的苯并硫氮杂卓成为广谱抗癌剂，而 2-噻吩基苯并硫氮杂卓和通过双迈克尔加成反应形成的副产物由于其对 NCI 的高度选择性活性而成为有希望进一步阐述的结构。 –H460肺癌细胞系。