DESIGN AND TESTING OF NOVEL CYTOTOXIC POLYAMINE ANALOGS

We designed three polyamine analogues, 1,14-diamino-N-5-methyl-5,10-di azatetradecane (5me-4-4-4), ,14-diamino-N-5,N-5-dimethyl-5,10-diazatet radecane (Q-Amm-4-4-4), and ethylamino)-N-5,N-5-dimethyl-5,10-diazatet radecane (BE-Q-Amm-4-4-4), on the basis of computer modeling and physi cal-chemical studies of polyamine-DNA interactions. These analogues di ffer from natural polyamines and from one another in the charge distri bution on their aliphatic backbone. We found that 10 eta M 5me-4-4-4 d id not inhibit growth and was not cytotoxic to tbe human brain tumor c ell lines SF-767 and SF-126. The same concentrations of Q-Amm-4-4-4 an d BE-Q-Amm-4-4-4 inhibited cell growth and killed more than 90% of eac h cell type on day 7 of the experiment. BE-Q-Amm-4-4-4 was slightly mo re toxic than Q-Amm-4-4-4 in both cell lines. All three agents either decreased or completely depleted intracellular putrescine and spermidi ne. Q-Amm-4-4-4 and BE-Q-Amm-4-4-4 each also lowered spermine. The fac t that 5me-4-4-4 was nontoxic but that Q-Amm-4-4-4 was cytotoxic and i nhibited growth suggests that the charge distribution along the surfac e of the aliphatic backbone of polyamines is important in determining growth inhibition and cytotoxicity.