在固态相合成的dysidiolide衍生的蛋白质酸酶抑制剂
Dirk Brohm1, Nicolas Philippe, Susanne Metzger
1Max-Planck-Institut für molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.
Journal of the American Chemical Society
|October 31, 2002
概括
像dysidiolide这样的天然产品可以作为开发新药化合物的出色起点. 这项研究使用固相合成成功合成了dysidiolide类似物,产生了抑制Cdc25C和显示抗癌活性的化合物.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
- 药物发现 药物发现 药物发现
背景情况:
- 生物活性天然产品为设计复合库提供了验证的起点.
- 在天然产品周围开发合成路径可以提高识别生物相关药物候选者的成功率.
研究的目的:
- 为了证明复杂的固相反应序列的成功开发,用于天然产品的模拟合成.
- 为了合成和生物评估蛋白质酸酶Cdc25抑制剂的类似物,dysidiolide.
主要方法:
- 固相合成涉及复杂的多步反应序列 (8-12个线性步骤).
- 利用了各种各样的有机反应,包括不对称的循环添加,有机金属转化,油脂化,氧化,水解和核替代.
- 从100毫克树脂中合成了八种dysidiolide类似物,获得了6%至27%的产量.
主要成果:
- 成功合成了8个多毫克的dysidiolide类似物.
- 合成的类似物抑制了Cdc25C在低微分子范围,IC50值以20的系数变化.
- 类似物在针对各种癌症细胞系的细胞毒性测定中表现出相当多和差异化的生物活性.
结论:
- 固相合成是一种可行的策略,用于产生复杂的天然产品,如dysidiolide的多种类型的类似物.
- 合成的dysidiolide类似物代表了进一步调查的有希望的线索,作为潜在的针对Cdc25C的抗癌剂.
- 这种方法验证了使用天然产品作为药物化学图书馆开发的支架.
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