Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives

A new means of accessing N-1-cyclopropylmethyl-N-11-ethylnorspermine (CPMENSPM) and the first synthesis of (2R, 10S)-N-1-cyclopropylmethyl-2, 10-dihydroxy-N-11-ethylnorspermine [(2R, 10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N-1,N-11-diethylnorspermine (DENSPM) or (2R, 10R)-N-1,N-11-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of(2S, 10S)-N-1,N-11-diethyl-2,10-dihydroxynorspermine [(2S, 10S)-(HO)2DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R, 10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/ spermine N-1-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R, 10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.