• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Chemistry: A European journal >Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90
【24h】

Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90

机译：探索玉米赤霉烯酮类似物中的烯丙基甲基对与Hsp90结合的影响

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

By the replacement of an acetate with propionate by means of organic synthesis, a range of zearalenone analogues were prepared that feature an allylic methyl group. For the synthesis of the aliphatic region of the analogues, we used an asymmetric alkylation to yield pentenol derivatives 16 and ent-16. By means of hydroboration the corresponding aldehydes were secured. These were coupled with 2-pentynol derivate 23 by means of a Carreira acetylide addition. Further routine steps led to the sulfones 29 and 45, respectively. After merging them with 2-bromobenzaldehyde 9 in a Julia-Kocienski reaction, metalation, carboxylation, and protecting-group manipulations gave the seco acids 35 and 49. By means of lactonization under Mitsunobu (alcohol activation) or Trost-Kita conditions (carboxyl activation), all four possible macrocyclic ketone stereoisomers were accessible. In all, considering various protecting-group decorations, 16 analogues were obtained and tested for cytotoxicity (L929 mouse fibroblast cell line). Whereas most of the analogues were less active than zearalenone (IC_(50)=9.4μM), the resorcinol derivatives were comparable, with one stereoisomer (40b) being slightly more active (IC_(50)=6.6μM). These results were also reflected in the binding assays to Hsp90 in which 40b showed a dissociation constant (K _d) value of 130nM. Gimme five: The preparation and testing of zearalenone analogues in which acetate number five was replaced by a propionate is reported. The shown stereoisomer was slightly more active in binding to Hsp90; studies show that the position and stereochemistry of a methyl-bearing center can cause a significant difference in binding (see scheme).
机译：通过有机合成用丙酸酯代替乙酸盐，制备了一系列具有烯丙基甲基的玉米赤霉烯酮类似物。对于类似物的脂肪族区域的合成，我们使用不对称烷基化反应生成戊烯醇衍生物16和ent-16。通过硼氢化反应，确保了相应的醛。通过加入Carreira乙炔化物将它们与2-戊炔醇衍生物23偶联。进一步的常规步骤分别导致了砜29和45。在Julia-Kocienski反应中将它们与2-溴苯甲醛9合并后，金属化，羧化和保护基操作产生了癸二酸35和49。通过在Mitsunobu（酒精活化）或Trost-Kita条件（羧基活化）下进行内酯化），所有四种可能的大环酮立体异构体均可用。总之，考虑到各种保护基修饰，获得了16个类似物并测试了细胞毒性（L929小鼠成纤维细胞系）。尽管大多数类似物的活性低于玉米赤霉烯酮（IC_（50）=9.4μM），但间苯二酚衍生物却具有可比性，其中一种立体异构体（40b）的活性稍高（IC_（50）=6.6μM）。这些结果也反映在与Hsp90的结合测定中，其中40b显示出130nM的解离常数（K_d）值。 Gimme 5：报道了玉米赤霉烯酮类似物的制备和测试，其中五号乙酸盐被丙酸酯替代。所示的立体异构体与Hsp90的结合活性更高。研究表明，甲基中心的位置和立体化学可导致结合力的显着差异（请参阅方案）。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号