Conformationally restricted analogues of N-1,N-14-bisethylhomospermine (BE-4-4-4): Synthesis and growth inhibitory effects on human prostate cancer cells

Twelve analogues of N-1,N-14-bisethylhomospermine (BE-4-4-4) with restricte d 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-su bstituted cyclopropane ring, a 1,2-substituted cyclobutane ring, and a 2-bu tene residue. In each case, the cis/trans-isomeric pair was synthesized. Ci s-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 fr om the tetraazaeicosane skeleton of BE-4-4-4 were also prepared. Four cultu red human prostate cancer cell lines (LnCap, DU145, DuPro, and PC-3) were t reated 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 intrace llular 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 log; of cells after 6 days of treatment at 10 muM. Four new tetramines, th e two cyclopropyl isomers, the trans-cyclobutyl isomer, and the (5Z)-tetraa zaeicosene, were more cytotoxic than their saturated counterpart (BE-4-4-4) . Their cytotoxicity, however, could not be correlated either with their ce llular uptake or with their ability to deplete intracellular polyamine pool s. We attribute their cytotoxicity to their specific molecular structures. The cytotoxicity was markedly reduced when the central butane segment was d eprived of its rotational freedom by replacing it with a double bond. Intro duction of a triple bond or a benzene-1,2-dimethyl residue at the central s egment of the polyamine chain, led to complete loss of biological activity. The conformationally restricted alicyclic derivatives were not only more c ytotoxic than was the freely rotating BE-4-4-4 by several orders of magnitu de but also had much lower systemic toxicities than the latter. Thus, we ob tained new tetramines with a wider therapeutic window than BE-4-4-4.