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Role of the Methylene Backbone in the Antiproliferative Activity of Polyamine Analogues on L1210 Cells

Department of Medicinal Chemistry, College of Pharmacy University of Florida, Gainesville, Florida 32610

The impact of the polyamine analogues, N¹,N¹¹-diethylnorspermine (DENSPM), N¹,N¹²-diethylspermine (DESPM), and N¹,N¹⁴-diethylhomospermine (DEHSPM) on the growth properties of L1210 murine leukemia cells is compared. The order of antiproliferative activity of the three compounds is shown to be DEHSPM > DESPM > DENSPM with average 96-h IC₅₀ values of 0.06, 0.18, and 1.3 µM, respectively. Trypan blue exclusion suggests that the cytotoxic behavior of the compounds is not apparent until 96 h after exposure to the analogues. DEHSPM is shown to act more quickly and demonstrates the most profound cytotoxic effects at 144 h. Competitive uptake studies with spermidine reveal DESPM and DEHSPM to have essentially identical K_i values of 1.4 and 1.6 µM, respectively, while DENSPM indicates a substantially higher K_i value of 17 µM. Finally, although the analogues reduce the levels of putrescine, spermidine, and spermine in L1210 cells, if the concentration of polyamines in the cell, including analogues, is expressed on a nitrogen equivalence basis, the total cationic charge with which the polyamines are associated is conserved.

Received 10/ 7/88. Revised 3/ 3/89. Accepted 3/ 8/89.

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