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Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo.
Beilstein Journal of Organic Chemistry ( IF 2.2 ) Pub Date : 2020-01-27 , DOI: 10.3762/bjoc.16.14 Alexander Sailer 1 , Franziska Ermer 1 , Yvonne Kraus 1 , Rebekkah Bingham 1 , Ferdinand H Lutter 1 , Julia Ahlfeld 1 , Oliver Thorn-Seshold 1
Beilstein Journal of Organic Chemistry ( IF 2.2 ) Pub Date : 2020-01-27 , DOI: 10.3762/bjoc.16.14 Alexander Sailer 1 , Franziska Ermer 1 , Yvonne Kraus 1 , Rebekkah Bingham 1 , Ferdinand H Lutter 1 , Julia Ahlfeld 1 , Oliver Thorn-Seshold 1
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Background: Hemithioindigo is a promising molecular photoswitch that has only recently been applied as a photoswitchable pharmacophore for control over bioactivity in cellulo. Uniquely, in contrast to other photoswitches that have been applied to biology, the pseudosymmetric hemithioindigo scaffold has allowed the creation of both dark-active and lit-active photopharmaceuticals for the same binding site by a priori design. However, the potency of previous hemithioindigo photopharmaceuticals has not been optimal for their translation to other biological models. Results: Inspired by the structure of tubulin-inhibiting indanones, we created hemithioindigo-based indanone-like tubulin inhibitors (HITubs) and optimised their cellular potency as antimitotic photopharmaceuticals. These HITubs feature reliable and robust visible-light photoswitching and high fatigue resistance. The use of the hemithioindigo scaffold also permitted us to employ a para-hydroxyhemistilbene motif, a structural feature which is denied to most azobenzenes due to the negligibly short lifetimes of their metastable Z-isomers, which proved crucial to enhancing the potency and photoswitchability. The HITubs were ten times more potent than previously reported hemithioindigo photopharmaceutical antimitotics in a series of cell-free and cellular assays, and allowed robust photocontrol over tubulin polymerisation, microtubule (MT) network structure, cell cycle, and cell survival. Conclusions: HITubs represent a powerful addition to the growing toolbox of photopharmaceutical reagents for MT cytoskeleton research. Additionally, as the hemithioindigo scaffold allows photoswitchable bioactivity for substituent patterns inaccessible to the majority of current photopharmaceuticals, wider adoption of the hemithioindigo scaffold may significantly expand the scope of cellular and in vivo targets addressable by photopharmacology.
中文翻译：
强大的基于半硫靛蓝的抗有丝分裂剂可控制纤维素中的微管细胞骨架。
背景：半硫靛蓝是一种有前途的分子光开关，直到最近才被用作控制纤维素生物活性的光开关药效团。独特地，与已应用于生物学的其他光开关相反，伪对称半硫靛蓝支架通过先验设计允许为相同的结合位点创建暗活性和轻活性光药物。但是，以前的半硫靛蓝光药物的效力对于将其翻译成其他生物学模型并不是最佳的。结果：受微管蛋白抑制性茚满酮结构的启发，我们创建了基于半硫靛蓝的茚满酮样微管蛋白抑制剂（HITubs），并优化了其作为抗有丝分裂光药物的细胞效能。这些HITub具有可靠且坚固的可见光光电开关和高抗疲劳性。半硫靛蓝支架的使用还使我们能够使用对羟基hemistilbene基序，由于其亚稳Z异构体的寿命短得可以忽略，因此大多数偶氮苯都拒绝了这种结构特征，事实证明这对增强效能和光开关性至关重要。在一系列无细胞和细胞试验中，HITubs的效价比以前报道的半硫靛蓝光药物有丝分裂剂强十倍，并且可以对微管蛋白聚合，微管（MT）网络结构，细胞周期和细胞存活进行强大的光控。结论：HITubs是用于MT细胞骨架研究的光药物试剂不断增长的工具箱的有力补充。另外，
更新日期：2020-01-27
中文翻译：
强大的基于半硫靛蓝的抗有丝分裂剂可控制纤维素中的微管细胞骨架。
背景：半硫靛蓝是一种有前途的分子光开关，直到最近才被用作控制纤维素生物活性的光开关药效团。独特地，与已应用于生物学的其他光开关相反，伪对称半硫靛蓝支架通过先验设计允许为相同的结合位点创建暗活性和轻活性光药物。但是，以前的半硫靛蓝光药物的效力对于将其翻译成其他生物学模型并不是最佳的。结果：受微管蛋白抑制性茚满酮结构的启发，我们创建了基于半硫靛蓝的茚满酮样微管蛋白抑制剂（HITubs），并优化了其作为抗有丝分裂光药物的细胞效能。这些HITub具有可靠且坚固的可见光光电开关和高抗疲劳性。半硫靛蓝支架的使用还使我们能够使用对羟基hemistilbene基序，由于其亚稳Z异构体的寿命短得可以忽略，因此大多数偶氮苯都拒绝了这种结构特征，事实证明这对增强效能和光开关性至关重要。在一系列无细胞和细胞试验中，HITubs的效价比以前报道的半硫靛蓝光药物有丝分裂剂强十倍，并且可以对微管蛋白聚合，微管（MT）网络结构，细胞周期和细胞存活进行强大的光控。结论：HITubs是用于MT细胞骨架研究的光药物试剂不断增长的工具箱的有力补充。另外，
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