Design and testing of novel cytotoxic polyamine analogues.
We designed three polyamine analogues, 1,14-diamino-N5-methyl-5,10- diazatetradecane (5me-4-4-4), 1,14-diamino-N5,N5-dimethyl-5,10-diazatetradecane (Q-Amm-4-4-4), and 1,14-bis-(ethylamino)-N5,N5-dimethyl-5,10-diazatetradecane (BE-Q-Amm-4-4-4), on the basis of computer modeling and physical-chemical studies of polyamine-DNA interactions. These analogues differ from natural polyamines and from one another in the charge distribution on their aliphatic backbone. We found that 10 microM 5me-4-4-4 did not inhibit growth and was not cytotoxic to the human brain tumor cell lines SF-767 and SF-126. The same concentrations of Q-Amm-4-4-4 and BE-Q-Amm-4-4-4 inhibited cell growth and killed more than 90% of each cell type on day 7 of the experiment. BE-Q-Amm-4-4-4 was slightly more toxic than Q-Amm-4-4-4 in both cell lines. All three agents either decreased or completely depleted intracellular putrescine and spermidine. Q-Amm-4-4-4 and BE-Q-Amm-4-4-4 each also lowered spermine. The fact that 5me-4-4-4 was nontoxic but that Q-Amm-4-4-4 was cytotoxic and inhibited growth suggests that the charge distribution along the surface of the aliphatic backbone of polyamines is important in determining growth inhibition and cytotoxicity.
Department of Neurological Surgery, University of California, San Francisco 94143.
H S
HS
Basu
L J
LJ
Marton
M
M
Pellarin
D F
DF
Deen
J S
JS
McManis
C Z
CZ
Liu
R J
RJ
Bergeron
B G
BG
Feuerstein
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000032:analysis; D001932:Brain Neoplasms / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D011073:Polyamines / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D011073:Polyamines