Amino-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones. Synthesis, antitumor activity, and quantitative structure--activity relationship.
Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.
Sami
S M
SM
Department of Pharmacology/Toxicology, University of Arizona, Tucson 85721.
Dorr
R T
RT
Sólyom
A M
AM
Alberts
D S
DS
Remers
W A
WA
D000225:Adenine; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002417:Cattle; D003110:Colonic Neoplasms / Q000188:drug therapy; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D007094:Imides / Q000494:pharmacology / Q000633:toxicity; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008942:Mitoxantrone / Q000494:pharmacology / Q000633:toxicity; D053644:Naphthalimides; D063065:Organophosphonates; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007094:Imides; D007546:Isoquinolines; D053644:Naphthalimides; D063065:Organophosphonates; C092761:azonafide; C037020:amonafide; D004317:Doxorubicin; D004247:DNA; D008942:Mitoxantrone; D000225:Adenine