title: 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.
abstract: 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.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
authors.forename: K W
authors.initials: KW
authors.lastname: Bair
authors.forename: C W
authors.initials: CW
authors.lastname: Andrews
authors.forename: R L
authors.initials: RL
authors.lastname: Tuttle
authors.forename: V C
authors.initials: VC
authors.lastname: Knick
authors.forename: M
authors.initials: M
authors.lastname: Cory
authors.forename: D D
authors.initials: DD
authors.lastname: McKee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D002911:Chrysenes / Q000138:chemical synthesis / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism*; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D011409:Propylene Glycols / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002911:Chrysenes; D007364:Intercalating Agents; D011409:Propylene Glycols; C056722:crisnatol; D004247:DNA