Synthetic polyamine analogues as antineoplastics
| Autor: | Allen H. Neims, Michael J. Ingeno, Thomas R. Hawthorne, John R. T. Vinson, Raymond J. Bergeron, James S. McManis, Rita Bortell |
|---|---|
| Rok vydání: | 1988 |
| Předmět: |
Male
Chemistry Spermine Biological activity Antineoplastic Agents Molecular biology DNA Mitochondrial chemistry.chemical_compound Mice Biochemistry Mice Inbred DBA Drug Discovery Polyamines Tumor Cells Cultured Molecular Medicine L1210 cells Animals Diethylnorspermine Trypan blue Viability assay Polyamine Leukemia L1210 DNA |
| Zdroj: | Journal of medicinal chemistry. 31(6) |
| ISSN: | 0022-2623 |
| Popis: | In this paper, we report on the synthesis and biological activity of a number of N-alkylated spermine compounds. The dialkylspermines N1,N12-dimethylspermine (DMSPM-2), N1,N12-diethylspermine (DESPM-3), and N1,N12-dipropylspermine (DPSPM-4) are all shown to inhibit the growth of L1210 cells in culture with IC50 values of less than 1 microM at 96 h. Furthermore, DESPM-3 is shown to be similarly active against Daudi and HL-60 cells in culture. A structure-activity relationship is shown to exist between the position at which spermine is alkylated and its antiproliferative properties. The activity of 10 microM DESPM-3 against L1210 cells was shown to be cytostatic, with greater than 90% cell viability by trypan blue exclusion, even after a 144-h exposure. When L1210 cells were treated with 10 microM DESPM-3 over a 144-h period, their size and mitochondrial DNA content were gradually but substantially diminished. However, flow cytometric measurements of the nuclear DNA content of these treated cells at 96 h indicated only slightly reduced S and G2 populations and significant changes only after 144 h. A cloning assay performed on the cells after 96 h of exposure to this drug (10 microM) indicated that the cells were not growing. Finally, when male DBA/2 mice, inoculated with L1210 leukemia cells, were treated with DESPM-3, their life span was increased in excess of 200% relative to untreated controls. Moreover, many long-term survivors were apparently tumor free at the end of the experiment (60 days). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|