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

以具有有效抗肿瘤活性的 OSW-1 作为先导化合物的新型抗癌药物的设计与合成

• 批准号: 15390004
• 负责人: NEMOTO Hideo
• 金额: $ 9.86万
• 依托单位: University of Toyama (2005)Toyama Medical and Pharmaceutical University (2003-2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390004/
• 关键词: OSW-1; antitumor activity; anticancer agent; steroid; structure-activity relationship; シスプラチン; オルトキノジメタン; ベンゾシクロブテン

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.

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。

项目成果

A Practical Asymmetric Synthesis of trans-4,5-Benzhydrindane-1-ones as a Precursor of A-Nor B-Aromatic Steroidal Compounds

作为 A-Nor B-芳香族甾族化合物前体的反式 4,5-二苯茚满-1-酮的实用不对称合成

• 发表时间: 2005
• 期刊: The Journal of Organic Chemistry 70(17)
• 作者: Yuji Matsuya;Yuji Matsuya
• 通讯作者: Yuji Matsuya

Synthesis and antitumor activity of the estrane analogue of OSW-1

• DOI: 10.1002/ejoc.200400632
• 发表时间: 2005-03
• 期刊: European Journal of Organic Chemistry
• 影响因子: 2.8
• 作者: Y. Matsuya;Seiji Masuda;N. Ohsawa;S. Adam;T. Tschamber;J. Eustache;K. Kamoshita;Y. Sukenaga;H. Nemoto*

Total Synthesis of A-Nor B-Aromatic OSW-1 Aglycon : A Highly Effective Approach to Optically Active trans-4,5-Benzhydrindane

A-Nor B-芳香族 OSW-1 苷元的全合成：光学活性反式-4,5-二苯茚烷的高效方法

• 发表时间: 2003
• 期刊: European Journal of Organic Chemistry (12)
• 作者: Yuji Matsuya;Takakatsu Itoh;Hideo Nemoto
• 通讯作者: Hideo Nemoto