RIBOFURANOSYL-BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF CASEIN KINASE-2 AND CASEIN KINASE-1
RIBOFURANOSYL-BENZIMIDAZOLE DERIVATIVES AS INHIBITORS OF CASEIN KINASE-2 AND CASEIN KINASE-1
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DOI：
10.1111/j.1432-1033.1990.tb15280.x
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发表时间：
1990-01-12
期刊：
影响因子：
--
通讯作者：
PINNA, LA
中科院分区：
文献类型：
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作者：
MEGGIO, F;SHUGAR, D;PINNA, LA
5，6-二氯-1-（β- D-呋喃核糖基）苯并咪唑（DiCl-RB）是酪蛋白激酶-2（CK-2）的强效抑制剂[Zandomeni，R. et.等人（1986）J.Biol.Chem.261，3414-3420]。在这里，DiCl-RB的一系列17种类似物已被用于研究该CK-2抑制剂家族的特异性和作用模式。苯环上的两个卤素取代基显示出在抑制中起显著的作用，5，6-二溴衍生物（DiBr-RB）比DiCl-RB有效五倍（Ki = 2 μ M cf. 10 μ M，以GTP为底物），而二氟衍生物（DiF-RB）几乎与未取代的1-（β- D-呋喃核糖基）苯并咪唑。另一方面，尽管核糖基团的一些修饰显著降低了抑制效率，但糖部分并不是严格需要的，因为二氯苯并咪唑本身（DiCl-Bz）是几乎与DiCl-RB一样好的抑制剂。DiCl-RB及其类似物（包括DiCl-Bz）对CK-2的抑制作用相对于核苷酸底物而言是竞争性的，其Ki值与GTP的关系低于与ATP的关系。最有效的抑制剂DiBr-RB与ATP和GTP的Ki值分别为6 μ M和2 μ M，表明对酶的亲和力高于对生理底物ATP和GTP的亲和力。已测定了DiBr-RB对CK-2以外的几种蛋白激酶的抑制能力。蛋白激酶-C，cAMP依赖性蛋白激酶，Ser/Thr蛋白激酶表达的伪狂犬病病毒，和四种不同的酪氨酸蛋白激酶从脾，证明不敏感的DiBr-RB浓度能够几乎完全抑制大鼠肝脏和玉米幼苗CK-2的活性。然而，酪蛋白激酶-1对DiBr-RB几乎与CK-2一样敏感。CK-1的抑制相对于ATP也是竞争性的（Ki = 14 μ M）。尽管各种类似物对CK-1的抑制谱与CK-2所观察到的相似，但核糖的5“-磷酸化显示了显著的差异，其增加了CK-2的Ki，而降低了CK-1的Ki。
5,6-Dichloro-1-(.beta.-D-ribofuranosyl)benzimidazole (DiCl-RB) is a powerful inhibitor of casein kinase-2 (CK-2) [Zandomeni, R. et. al. (1986) J. Biol. Chem. 261, 3414-3420]. Here a series of 17 analogues of DiCl-RB has been employed for studying the specificity and the mode of action of this family of CK-2 inhibitors. The two halogen substituents on the benzene ring are shown to play a prominent role in inhibition, the 5,6-dibromo derivative (DiBr-RB) being fivefold more effective than DiCl-RB (Ki = 2 .mu.M cf. 10 .mu.M, with GTP as substrate), whereas the difluoro derivative (DiF-RB) is nearly as ineffective as unsubstituted 1-(.beta.-D-ribofuranosyl)benzimidazole. On the other hand, although some modifications of the ribose group significantly decrease the inhibitory efficiency, the sugar moiety is not strictly required, since dichlorobenzimidazole itself (DiCl-Bz) is an inhibitor almost as good as DiCl-RB. Inhibition of CK-2 by DiCl-RB and by its analogues, DiCl-Bz included, is of the competitive type with respect to the nucleotide substrate, the Ki values being lower with GTP than with ATP. The Ki values of the most potent inhibitor, DiBr-RB, with ATP and GTP, are 6 .mu.M and 2 .mu.M, respectively, denoting an affinity for the enzyme higher than that of the physiological substrates, ATP and GTP. DiBr-RB has been assayed for its inhibitory capacity toward several protein kinase other than CK-2. Protein kinase-C, cAMP-dependent protein kinase, the Ser/Thr protein kinase expressed by pseudorabies virus, and four different tyrosine protein kinases from spleen, proved insensitive to DiBr-RB concentrations capable of almost entirely suppressing the activity of rat liver and maize seedling CK-2. Casein kinase-1 however is nearly as sensitive as CK-2 to DiBr-RB. Inhibition of CK-1 is also of the competitive type with respect to ATP (Ki = 14 .mu.M). Although the inhibitory spectrum of CK-1 by the various analogues is reminiscent of that observed with CK-2, a remarkable difference is revealed by 5''-phosphorylation of ribose which increases the Ki with CK-2 while decreasing that with CK-1.