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

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 sys...

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Published inJournal 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
LanguageEnglish
Published United States American Chemical Society 01.07.1991
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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.
AbstractList 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.
Author Knick, Vincent C
Cory, Michael
McKee, David D
Andrews, C. Webster
Tuttle, Richard L
Bair, Kenneth W
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Snippet The effects of variation of aromatic ring size, shape, and side-chain position on antitumor activity and DNA binding in a series of carbocyclic...
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SubjectTerms 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
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
URI http://dx.doi.org/10.1021/jm00111a010
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