Twelve analogues of 1N,14N-bisethylhomospermine (BE-4-4-4) with restricted conformations were synthesized in the search for
cancer chemotherapeutic agents with higher cytotoxic activities and lower systemic toxicities than
BE-4-4-4. The central
butane segment of
BE-4-4-4 was replaced with a 1,2-substituted
cyclopropane ring, a 1,2-substituted cyclobutane ring, and a
2-butene residue. In each case, the cis/trans-isomeric pair was synthesized. Cis-monounsaturation(s) was also introduced at the outer
butane segment(s) of
BE-4-4-4. The two possible cis-dienes and a cis-triene formally derived from the tetraazaeicosane skeleton of
BE-4-4-4 were also prepared. Four cultured human
prostate cancer cell lines (LnCap, DU145, DuPro, and PC-3) were treated with the new tetramines to examine their effects on cell growth with a MTT assay. One representative cell line (DuPro) was selected to further study the cellular uptake of the novel tetramines, their effects on intracellular
polyamine pools, and their cytotoxicity. All tetramines entered the cells, reduced cellular
putrescine and
spermidine pools while exerting only a small effect on the
spermine pool, inhibited cell growth, and killed 2-3 logs of cells after 6 days of treatment
at 10 microM. Four new tetramines, the two cyclopropyl isomers, the trans-cyclobutyl isomer, and the (5Z)-tetraazaeicosene, were more cytotoxic than their saturated counterpart (BE-4-4-4). Their cytotoxicity, however, could not be correlated either with their cellular uptake or with their ability to deplete intracellular
polyamine pools. We attribute their cytotoxicity to their specific molecular structures. The cytotoxicity was markedly reduced when the central
butane segment was deprived of its rotational freedom by replacing it with a double bond. Introduction of a triple bond or a benzene-1,2-dimethyl residue at the central segment of the
polyamine chain, led to complete loss of
biological activity. The conformationally restricted alicyclic derivatives were not only more cytotoxic than was the freely rotating
BE-4-4-4 by several orders of magnitude but also had much lower systemic toxicities than the latter. Thus, we obtained new tetramines with a wider therapeutic window than
BE-4-4-4.