Role of the colchicine ring a and its methoxy groups in the binding to tubulin and microtubule inhibition
Role of the colchicine ring a and its methoxy groups in the binding to tubulin and microtubule inhibition
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DOI：
10.1021/bi9728553
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发表时间：
1998-06-09
期刊：
影响因子：
2.9
通讯作者：
Timasheff, SN
中科院分区：
文献类型：
--
作者：
Andreu, JM;Perez-Ramirez, B;Timasheff, SN
通过合成一些药物并检测它们对微管蛋白结合、微管组装抑制和GT3活性诱导的影响，探讨了二环秋水仙碱（COL）类似物A环上甲氧基取代基的作用。在位置2、3和4处选择性消除环A甲氧基削弱了所有三个过程。对结合和抑制的影响与环C（或C '）的性质无关。具体地，切除2-或3-甲氧基基团通过约100%的量减弱结合。0.4 kcal mol（-1），而环A的4-甲氧基基团减弱了1.36 +/- 0.15 kcal mol（-1）。对微管组装的抑制作用，以微管蛋白-药物复合物与微管末端结合的平衡常数表示，更为复杂，并强烈依赖于环C（或C '）的性质。这归因于环C'上的各种基团克服由环A提供的锚定的减弱所引入的微管蛋白-药物复合物中的摆动的能力。因此，COL的A环与抑制微管蛋白自组装的机制没有密切关系。它仅作为复合物稳定锚。该过程的控制在于COL的C环或结构类似物的C'环的关键氧原子与蛋白质建立的相互作用。有人提出，环A的4-甲氧基基团作为一个关键的连接点，用于固定的药物对蛋白质。
The roles of the methoxy substituents on ring A of two ring colchicine (COL) analogues were probed by the synthesis of a number of drugs and the examination of their effect on binding to tubulin, inhibition of microtubule assembly, and induction of GTPase activity. Selective elimination of ring A methoxy groups at positions 2, 3, and 4 weakened all three processes. The effects on binding and inhibition were independent of the nature of ring C (or C'). Specifically, excision of the 2- or 3-methoxy groups weakened binding by ca. 0.4 kcal mol(-1), while that of the 4-methoxy group of ring A was weakened by 1.36 +/- 0.15 kcal mol(-1). The effect on the inhibition of microtubule assembly, expressed as the equilibrium constant for the binding of the tubulin-drug complex to the end of a microtubule, was more complex and strongly dependent on the nature of ring C (or C'). This was attributed to the abilities of various groups on ring C' to overcome the wobbling in the tubulin-drug complex introduced by the weakening of the anchoring provided by ring A. It is concluded that ring A of COL is not germane to the mechanism of the inhibition of tubulin self-assembly. It serves only as a complex-stabilizing anchor. The control of this process resides in the interactions that key oxygen atoms of ring C of COL or C' of structural analogues establish with the protein. It is proposed that the 4-methoxy group of ring A serves as a key attachment point for immobilization of the drugs on the protein.