2-[(Arylmethyl)amino]-2-methyl-1,3-propanediol DNA intercalators. An examination of the effects of aromatic ring variation on antitumor activity and DNA binding

• Published in: Journal of medicinal chemistry Vol. 34; no. 7; pp. 1983 - 1990
• Main Authors: Bair, Kenneth W, Andrews, C. Webster, Tuttle, Richard L, Knick, Vincent C, Cory, Michael, McKee, David D
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.07.1991
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Chemical Phenomena; Chemistry; Chrysenes - chemical synthesis; Chrysenes - therapeutic use; DNA - metabolism; Intercalating Agents - chemical synthesis; Intercalating Agents - therapeutic use; Leukemia P388 - drug therapy; Mice; Propylene Glycols - chemical synthesis; Propylene Glycols - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00111a010

The effects of variation of aromatic ring size, shape, and side-chain position on antitumor activity and DNA binding in a series of carbocyclic 2-[(arylmethyl)amino]-2-methyl-1,3-propanediols (AMAPs) were examined. In general, the interaction of AMAPs with DNA increases as the intercalating ring system grows in area, with three distinct binding levels evident. Isomers from a specific ring system appear to bind DNA similarly. DNA binding is not the sole criterion for antitumor activity for the AMAPs studied; the magnitude of the delta Tm does not correlate with the antitumor activity observed. Significant in vivo P388 activity was seen for AMAP congeners from several tetracyclic ring systems. However, isomers from each of the specific ring systems produced a wide range of in vivo P388 activity. Thus, AMAP antitumor activity is not a function of the ring system per se, but rather appears to be related to the shape of the specific molecule. Three AMAP congeners (crisnatol (770U82, 773U82, and 502U83) are currently in clinical trials.