Synthetic polyamine analogues as antineoplastics.
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).
Bergeron
R J
RJ
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville 32610.
Neims
A H
AH
McManis
J S
JS
Hawthorne
T R
TR
Vinson
J R
JR
Bortell
R
R
Ingeno
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000032:analysis; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000032:analysis / Q000187:drug effects
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D011073:Polyamines