Cis-unsaturated analogues of 3,8,13,18,23-pentaazapentacosane (BE-4-4-4-4): Synthesis and growth inhibitory effects on human prostate cancer cell lines

From the results of our previous physicochemical studies of polyamine-nucle ic acid interactions, we concluded that polyamine analogues in cisoidal con formation are capable of wrapping around the major groove of the double hel ix, of displacing natural polyamines from their nucleic acid binding sites, and of inhibiting cell division. On the basis of this hypothesis, nine uns aturated pentamines, formally derived from the cytotoxic pentamine 3,8,13,1 8,23-pentaazapentacosane (BE-4-4-4-4), were prepared in an attempt to incre ase antineoplastic activity. Cis-double bonds were introduced in all possib le sites in the saturated pentaazapentacosane structure of BE-4-4-4-4 to yi eld two pentacosenes, four pentacosadienes, two pentacosatrienes, and one p entacosatetraene. Cis-double bonds should also provide good targets for mix ed-function oxidases that might eliminate the accumulation of unsaturated p entamines in serum, thereby reducing systemic toxicity in animals. We deter mined the ability of these new pentamines to inhibit growth in four culture d human prostate cancer cell lines (LnCap, DU145, PC-3, and DuPro) using a MTT assay. LnCap and DU145 cells were very sensitive, PC-3 cells were relat ively resistant, and DuPro cells were intermediate in sensitivity to most o f these synthetic pentamines. In all cell lines, pentamines that had unsatu ration(s) at the end of the chain showed the highest cell growth inhibitory effects. The cellular uptake, effects on cellular polyamine levels, and cy totoxicity of these pentamines on one representative prostate cancer cell l ine (DuPro) were further examined with a colony-forming efficiency (CFE) as say. The pentamines with unsaturation(s) at the end of the chain were once again the most cytotoxic among both the saturated (BE-4-4-4-4) and unsatura ted analogues. Appreciable amounts of all pentamines entered DuPro cells an d depleted cellular polyamine pools by day 6 of treatment. For most pentami nes, however, cell growth inhibitory and cytotoxic effects could not be dir ectly correlated either with their cellular uptake or with their ability to deplete cellular polyamine pools. The position of the double bonds in the aliphatic backbone seems to be the most important determinant of cytotoxici ty. For some pentamines, however, depletion of cellular polyamines may add to their efficacy.