Conformationally Restricted Analogues of ¹N,¹⁴N-Bisethylhomospermine (BE-4-4-4):  Synthesis and Growth Inhibitory Effects on Human Prostate Cancer Cells

Abstract

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.

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…Although inhibitors of virtually all of the biosynthetic enzymes in polyamine metabolism have been synthesized, none has demonstrated clinical efficacy as a single agent in clinical trails for cancer (see [20]). In an attempt to overcome the limitations encountered with specific inhibitors of enzyme function, we and others have exploited the self-regulatory properties of polyamine metabolism for therapeutic advantage through the use of structural analogues of the natural polyamines [4,5,8,18,39,43,44,49]. The initial studies with polyamine analogues, particularly with BENSpm, were promising, but clinical trials with a number of analogues in lung, breast, and other tumors did not reveal efficacy as single agents.…”

The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib

“…Based on this success, novel combination therapies with bortezomib are being tested for efficacy and for their potential in circumventing drug resistance in MM. CGC-11093 is a novel polyamine analogue that has completed a phase I trial for the treatment of cancer (14,15). Given the important role of polyamines in pathways targeted by the mechanism of action of bortezomib, we hypothesized that CGC-11093 may enhance its therapeutic efficacy.…”

Activities ofdl-α-Difluoromethylarginine and Polyamine Analogues againstCryptosporidium parvumInfection in a T-Cell Receptor Alpha-Deficient Mouse Model

“…It was found that CGC-11047 is more effective in prevention than in curing an established infection, which we propose is due to the ability of this group of analogues to upregulate host cell SSAT, resulting in the overproduction of acetylated polyamines (17) and their resultant excretion into the lumen of the gut from where it is voided, making it unavailable to the parasite. By comparison, the 4-4-4 analogues such as CGC-11157 do not induce host cell SSAT (18,27), and their effect is directly on the parasite SSAT, confirming previous studies that demonstrated that parasite SSAT is significantly inhibited by this group of inhibitors (36). Our results of SSAT activity in control and CGC-11157-treated mouse intestinal tissues agree with previous results demonstrating that SSAT activity does not change with exposure to this compound (Table 5).…”

“…The synthesis of oligoamines was carried out as described previously. Briefly, N 1 -monoethyl tetramides in which the amino groups were protected by a mesitylenesulfonyl residue (18,27) were dimerized by reactions with (E)-or (Z)-2-butene-1,4-diyl-bis(mesitylenesulfonate) to give the corresponding octamide. The protecting group was then removed, and the oligoamine was isolated as the hydrochloride.…”