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

Abstract

From the results of our previous physicochemical studies of polyamine-nucleic acid interactions, we concluded that polyamine analogues in cisoidal conformation are capable of wrapping around the major groove of the double helix, of displacing natural polyamines from their nucleic acid binding sites, and of inhibiting cell division. On the basis of this hypothesis, nine unsaturated pentamines, formally derived from the cytotoxic pentamine 3,8,13,18,23-pentaazapentacosane (BE-4-4-4-4), were prepared in an attempt to increase antineoplastic activity. Cis-double bonds were introduced in all possible sites in the saturated pentaazapentacosane structure of BE-4-4-4-4 to yield two pentacosenes, four pentacosadienes, two pentacosatrienes, and one pentacosatetraene. Cis-double bonds should also provide good targets for mixed-function oxidases that might eliminate the accumulation of unsaturated pentamines in serum, thereby reducing systemic toxicity in animals. We determined the ability of these new pentamines to inhibit growth in four cultured 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 relatively resistant, and DuPro cells were intermediate in sensitivity to most of these synthetic pentamines. In all cell lines, pentamines that had unsaturation(s) at the end of the chain showed the highest cell growth inhibitory effects. The cellular uptake, effects on cellular polyamine levels, and cytotoxicity of these pentamines on one representative prostate cancer cell line (DuPro) were further examined with a colony-forming efficiency (CFE) assay. 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 unsaturated analogues. Appreciable amounts of all pentamines entered DuPro cells and depleted cellular polyamine pools by day 6 of treatment. For most pentamines, however, cell growth inhibitory and cytotoxic effects could not be directly 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 cytotoxicity. For some pentamines, however, depletion of cellular polyamines may add to their efficacy.

Recent Advances in the Development of Polyamine Analogues as Antitumor Agents

“…In addition, insertion of a cis double bond into the terminal aminobutyl moieties of 9 (i.e. as in CGC-11121, 20 and CGC-11128, 21 , Figure 5) also affords analogues that are equipotent to 9 with respect to ID 50 values, but that are an order of magnitude more cytotoxic in a dose-response study 63. Recently, cis - 14 was shown to effectively inhibit the growth of both small cell (NCI H82 and H69) and non-small cell (NCI A549 and H157) lung cancer cells in vitro 64.…”

Molecular Symmetry: A Structural Property Frequently Present in New Cytotoxic and Proapoptotic Drugs

“…Numerous ideas have been put forward to explain their mechanism of action [114,115] and these include induction of apoptosis [116], induction of acetylCoA:spermidine N 1 -acetyltransferase [117], interaction with nucleic acids [118] (which is one of the more compelling), mitochondriotoxicity [119] and calmodulin antagonism [120] among others. The most widely assayed cytotoxic polyamine analogs have been tetra-or pentamines [121][122][123][124] and, more recently, there has been great interest in exploring the antiproliferative activity of their higher homologs [125], such as octamines, decamines, dodecamines and tetradecamines, which are named "oligoamines". These "oligoamines" (Fig.…”

Properties of the Spermidine/SpermineN1-Acetyltransferase Mutant L156F That Decreases Cellular Sensitivity to the Polyamine AnalogueN1,N11-Bis(ethyl)norspermine

“…Since that time, a wide variety of structural polyamine analogues have been synthesized with modifications to the natural polyamine structures that include small symmetrical terminal substituents, large unsymmetrical terminal substituents, increased or decreased internal carbon chain lengths, the introduction of sites of unsaturation in the internal carbon chains, and even the linking together of two or more of these altered structures (5,10,11). Results from testing in cell systems also have been widely varied and, unfortunately, few clear cut structure/function relationships have been discernible.…”