Design and Synthesis of New Anticancer Agents Based on OSW-1 Having Potent Antitumor Activity as a Lead Compound

本论文以甾体皂苷OSW-1为基础，设计、合成并评价了一种新的抗肿瘤药物。为此目的，设计了具有简化的甾体糖基的新型OSW-1类似物，并且从市售的雌酮开始成功地合成了A-芳香型糖基。将天然OSW-1中发现的二糖部分引入A-芳香糖苷配基，并对由此获得的OSW-1类似物进行抗肿瘤活性评价。这表明，类似物表现出显着的活性与顺铂，临床上使用的抗癌剂相当的效力。合成了几种具有不同二糖结构的类似物，并发现一种含氟衍生物具有显著的抗肿瘤活性。在此基础上设计了进一步简化的甾体苷元，即A-或B-芳香苷元。该合成是利用连续的周环反应，通过苯并环丁烯衍生物的电环裂解作为一个关键反应，具有良好的立体选择性。安装的二糖部分的A-或B-芳族糖苷配基目前正在调查中，并计划在未来的结构-活性关系的研究，从而获得的OSW-1类似物。

Based on a potent antitumor steroidal saponin OSW-1,design, synthesis, and biological evaluation of new candidate for a clinically useful anticancer agent were performed. For this purpose, novel OSW-1 analogues, which have a simplified steroidal sglycon, were designed, and A-aromatic type of aglycon was synthesized successfully starting from commercially available estrone. Dissacharide moiety found in natural OSW-1 was introduced to the A-aromatic aglycon, and the OSW-1 analogue thus obtained was subjected to the evaluation of antitumor activity. This revealed that the analogue exhibited notable activity with a comparable potency to cisplatin, clinically used anticancer agent. Several analogues having different disaccharide structure were also synthesized, and it was found that a fluoro-containing derivative showed significant antitumor activity. Based on these results, further simplified steroidal aglycon, namely A-nor B-aromatic aglycon, was designed. The synthesis was accomplished using successive pericyclic reactions via electrocyclic cleavage of benzocyclobutene derivatives as a key reaction with an excellent stereoselectivity. Installation of a disaccharide moiety to the A-nor B-aromatic aglycon is now under investigation, and a structure-activity relationship study of the OSW-1 analogues thus obtained are planned in future.