Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring.
Development of a novel class of tubulin inhibitor from desmosdumotin B with a hydroxylated bicyclic B-ring.
复制标题
用羟基化双环B环从去肿瘤蛋白B中开发出新的微管蛋白抑制剂。
DOI：
10.1021/jm501859j
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发表时间：
2015-03-12
影响因子：
7.3
通讯作者：
Goto M
中科院分区：
文献类型：
--
作者：
Nakagawa-Goto K;Oda A;Hamel E;Ohkoshi E;Lee KH;Goto M
一系列新合成的具有双环B环的桥桥素B(TEDB)羟基类似物在影响微管动力学和纺锤体形成方面表现出显著不同的作用模式，但具有相同的抗增殖活性谱，包括对多药耐药肿瘤的活性。这些类似物有效地诱导细胞周期停滞于前中期，并导致未成熟的多极纺锤体的形成。6‘-羟基TEDB-Tb(8)破坏了双极纺锤体的形成，但对相间微管的影响很小。根据预测的新化合物与微管蛋白二聚体的结合方式，化合物4仅与秋水仙素位置的α-微管蛋白形成三个氢键(H键)；相反，化合物8与α-和β-微管蛋白都形成氢键。我们预测，当一个化合物/配体，如8，在α-和β-微管蛋白上形成氢键时，纺锤体的形成比相间微管的动力学受到更大的破坏。这一结果可能反映了众所周知的纺锤形微管比间期微管更具活力。
A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6′-Hydroxyl TEDB-TB (8) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound 4 forms three hydrogen bonds (H-bonds) only with α-tubulin at the colchicine site; in contrast, 8 forms H-bonds with both α- and β-tubulin. We predict that, when a compound/ligand, such as 8, forms H-bonds to both α- and β-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules.
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影响因子：
5.6
作者：
JONES, G;WILLETT, P;GLEN, RC
通讯作者：
GLEN, RC
影响因子：
7.3
作者：
Nakagawa-Goto K;Wu PC;Lai CY;Hamel E;Zhu H;Zhang L;Kozaka T;Ohkoshi E;Goto M;Bastow KF;Lee KH
通讯作者：
Lee KH
影响因子：
3.5
作者：
Matsunaga, N;Kaku, T;Tasaka, A
通讯作者：
Tasaka, A
影响因子：
3.7
作者：
Yeh, JJ;Hsu, WH;Kao, A
通讯作者：
Kao, A
影响因子：
2.1
作者：
Chabert, JFD;Joucla, L;Lemaire, M
通讯作者：
Lemaire, M