Lu J, Chen Z P, Yan Y P, Knapp S, Schugar H, Chen K Y
Department of Chemistry, Rutgers University, The State University of New Jersey,Piscataway, NJ 08854-8087, USA.
Cancer Lett. 2000 Nov 10;160(1):59-66. doi: 10.1016/s0304-3835(00)00561-9.
Deoxyhypusine synthase is the key enzyme for modifying a lysine residue to hypusine in the cellular protein eukaryotic initiation factor 5A (eIF-5A). Deletion of the deoxyhypusine synthase or the eIF-5A gene in yeast produces lethal phenotype. Inhibition of deoxyhypusine synthase by 1-guanidino-7-aminoheptane (GC7) suppresses tumor cell growth. Hypusine formation represents one of the most specific polyamine-dependent biochemical reactions. In view of the importance of polyamines in growth regulation and cancer biology, deoxyhypusine synthase has been considered to be a good target for chemotherapeutic drug design. Using GC7 as a prototype we have synthesized and tested three classes of diamine analogs, namely, guanidino-, pyrimidino-, and hydroxamate derivatives, as potential inhibitors for deoxyhypusine synthase. Our study shows that (i) among all the compounds tested, GC7 remained to be the most potent inhibitor for deoxyhypusine synthase; (ii) N,N'-bispyrimidino-1, 9-diaminononane, although a poor inhibitor of deoxyhypusine synthase, was a potent growth inhibitor; and (iii) one of the hydroxamate derivatives, 6-aminohexanoic hydroxamate (HC6), prominently induced the differentiation of mouse neuroblastoma cells at sub-millimolar concentrations. Interestingly, other hydroxamates with different chain length were not nearly as effective as HC6 in inducing neuroblastoma cell differentiation. The effect of HC6 was also unique in that it could induce neurite outgrowth and the expression of neuron-specific genes such as synapsin I and MAP-2 in neuroblastoma cells in the absence of other promoting agents such as cAMP. The effect of HC6 on neuroblastoma cell differentiation was comparable with, or better than that of N(6),O(2)'-dibutyryl cAMP (Bt(2)cAMP), a standard reagent commonly used for inducing the differentiation of mouse and human neuroblastoma cells in culture.
脱氧hypusine合成酶是将细胞蛋白真核起始因子5A（eIF-5A）中的赖氨酸残基修饰为hypusine的关键酶。在酵母中缺失脱氧hypusine合成酶或eIF-5A基因会产生致死表型。1-胍基-7-氨基庚烷（GC7）对脱氧hypusine合成酶的抑制作用可抑制肿瘤细胞生长。Hypusine的形成是最特殊的多胺依赖性生化反应之一。鉴于多胺在生长调节和癌症生物学中的重要性，脱氧hypusine合成酶被认为是化疗药物设计的一个良好靶点。以GC7为原型，我们合成并测试了三类二胺类似物，即胍基、嘧啶基和异羟肟酸酯衍生物，作为脱氧hypusine合成酶的潜在抑制剂。我们的研究表明：（i）在所有测试的化合物中，GC7仍然是脱氧hypusine合成酶最有效的抑制剂；（ii）N，N'-双嘧啶基-1，9-二氨基壬烷虽然是脱氧hypusine合成酶的弱抑制剂，但却是一种有效的生长抑制剂；（iii）一种异羟肟酸酯衍生物6-氨基己酸异羟肟酸酯（HC6）在亚毫摩尔浓度下能显著诱导小鼠神经母细胞瘤细胞分化。有趣的是，其他具有不同链长的异羟肟酸酯在诱导神经母细胞瘤细胞分化方面远不如HC6有效。HC6的作用也很独特，因为在没有其他促进剂如cAMP的情况下，它能诱导神经母细胞瘤细胞长出神经突并表达神经元特异性基因，如突触素I和MAP-2。HC6对神经母细胞瘤细胞分化的作用与N（6），O（2）'-二丁酰cAMP（Bt（2）cAMP）相当，或优于Bt（2）cAMP，Bt（2）cAMP是在培养中常用于诱导小鼠和人类神经母细胞瘤细胞分化的标准试剂。
