Aminohexanoic hydroxamate is a potent inducer of the differentiation of mouse neuroblastoma cells

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 produce s lethal phenotype. Inhibition of deoxyhypusine synthase by 1-guanidino-7-a minoheptane (GC7) suppresses tumor cell growth. Hypusine formation represen ts one of the most specific polyamine-dependent biochemical reactions. In v iew of the importance of polyamines in growth regulation and cancer biology , deoxyhypusine synthase has been considered to be a good target for chemot herapeutic drug design. Using GC7 as a prototype we have synthesized and re sted three classes of diamine analogs, namely, guanidino-, pyrimidino-. and hydroxamate derivatives, as potential inhibitors for deoxyhypusine synthas e. Our study shows that (i) among all the compounds tested, GC7 remained to be the most potent inhibitor for deoxyhypusine synthase; (ii) N,N'-bispyri midino-1,9-diaminononane. although a poor inhibitor of deoxyhypusine syntha se, was a potent growth inhibitor; and (iii) one of the hydroxamate derivat ives, 6-aminohexanoic hydroxamate (HC6), prominently induced the differenti ation of mouse neuroblastoma cells at sub-millimolar concentrations. Intere stingly, 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 e xpression of neuron-specific genes such as synapsin I and MAP-2 in neurobla stoma cells in the absence of other promoting agents such as cAMP. The effe ct of HC on neuroblastoma cell differentiation was comparable with, or bett er than that of N-6,O-2'-dibutyryl cAMP (Bt(2)cAMP), a standard reagent com monly used for inducing the differentiation of mouse and human neuroblastom a cells in culture. (C) 2000 Elsevier Science Ireland Ltd. All rights reser ved.