A COMPARISON OF STRUCTURE-ACTIVITY-RELATIONSHIPS BETWEEN SPERMIDINE AND SPERMINE ANALOG ANTINEOPLASTICS

A systematic investigation of the impact of spermidine analogues both in vitro and in vivo is described. The study characterizes the effects of these analogues on L1210 cell growth, polyamine pools, ornithine d ecarboxylase, S-adenosyl-L-methionine decarboxylase, spermidine/spermi ne N-1-acetyltransferase, the maintenance of cellular charge, i.e., ca tionic equivalence associated with the polyamines and their analogues, and compares their ability to compete with spermidine for transport. The findings clearly demonstrate that the activity of-the linear polya mine analogues is highly dependent on the length of the triamines and the size of the N-alpha,N-omega-substituents. It appears that there is an optimum chain length for various activities and that the larger th e N-alpha,N-omega-alkyls, the less active the compound. Metabolic tran sformation including N-dealkylation of these compounds is also evaluat ed. While there is no monotonic relationship between chain length and the ability of the analogue to be metabolized, the dipropyl triamines are clearly more actively catabolized than the corresponding methyl an d ethyl systems. A comparison of the triamines with the corresponding tetraamines is made throughout the text regarding both in vitro activi ty against L1210 cells and in vivo toxicity measurements, suggesting t hat several triamine analogues may offer therapeutic advantages over t he corresponding tetraamines.