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

• Published in: Journal of medicinal chemistry 2001-02, Vol.44 (3), p.404-417
• Main Authors: Reddy, Venodhar K, Sarkar, Aparajita, Valasinas, Aldonia, Marton, Laurence J, Basu, Hirak S, Frydman, Benjamin
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Drug Screening Assays, Antitumor; General aspects; Humans; Magnetic Resonance Spectroscopy; Male; Medical sciences; Pharmacology. Drug treatments; Prostatic Neoplasms; Spermine - analogs & derivatives; Spermine - chemical synthesis; Spermine - chemistry; Spermine - pharmacology; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000310s

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.