(1-Pyrenylmethyl)amino alcohols, a new class of antitumor DNA intercalators. Discovery and initial amine side chain structure-activity studies.
In the series of 1-pyrenylmethylamines studied in this work the relationships among structure, interaction with DNA, and murine antitumor activity were examined. Binding studies show that all of these 1-pyrenylmethylamine derivatives bind to some extent to DNA by intercalation. The presence of additional basic amine groups in the side chain enhances DNA binding due to electrostatic interactions. Those compounds containing only a single basic benzylic amine bind similarly to DNA. Only the presence of bulky side chains appears to decrease the DNA interactions in the compounds examined. Although antitumor activity is seen for (1-pyrenylmethyl)amino alcohols, useful antitumor activity in the series is limited to those congeners bearing the 2-amino-1,3-propanediol-type side chain. These derivatives bind moderately to DNA. DNA binding is a necessary but not sufficient criterion for antitumor activity in the series. In addition, the strength of DNA binding does not correlate with the antitumor activity in the group of active compounds. Three related 2-[(arylmethyl)amino]-1,3-propanediol derivatives (AMAPs) [crisnatol (770U82), 773U82, and 502U83] are currently in clinical trials as potential antitumor agents.
Bair
K W
KW
Division of Organic Chemistry, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
Tuttle
R L
RL
Knick
V C
VC
Cory
M
M
McKee
D D
DD
D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D011721:Pyrenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000605:Amino Alcohols; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D011721:Pyrenes; D004247:DNA