Streptonigrin and lavendamycin partial structures. Probes for the minimum, potent pharmacophore of streptonigrin, lavendamycin, and synthetic quinoline-5,8-diones

• Published in: Journal of medicinal chemistry 1987-10, Vol.30 (10), p.1918-1928
• Main Authors: Boger, Dale L, Yasuda, Masami, Mitscher, Lester A, Drake, Steven D, Kitos, Paul A, Thompson, Sandra Collins
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - analysis; Antibiotics, Antineoplastic - therapeutic use; Chemical Phenomena; Chemistry; Chemistry, Physical; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Leukemia L1210 - drug therapy; Melanoma - drug therapy; Mice; Microbial Sensitivity Tests; Organic chemistry; Preparations and properties; Quinolines; Streptonigrin - analogs & derivatives; Streptonigrin - analysis; Streptonigrin - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00393a040

The preparation and evaluation of 7-amino-5,8-dioxo-2-(2'-pyridyl)quinoline-6'-carboxylic acid (5a) and 7-amino-2-(2'-aminophenyl)-5,8-dioxoquinoline-5'-carboxylic acid (6a) constituting potential minimum, potent pharmacophores of streptonigrin (1a) and lavendamycin (2a), two structurally related naturally occurring antitumor antibiotics, are detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-ring C-6' carboxylic acid potentiates the antitumor, antimicrobial, and cytotoxic properties of the naturally occurring, substituted 7-aminoquinoline-5,8-dione AB ring systems, the C-6'/C-5' carboxylic acid of 5a/6a diminishes the observed antimicrobial and cytotoxic properties of the 2-(2'-pyridyl)- and 2-(2'-aminophenyl)-7-aminoquinoline-5,8-diones. A direct comparison of the antimicrobial and cytotoxic properties of a complete set of streptonigrin and lavendamycin partial structures is detailed in efforts to define the role peripheral substituents play in potentiating the biological properties of the naturally occurring and synthetic agents bearing the 7-aminoquinoline-5,8-dione AB ring system and in efforts to define the minimum, potent pharmacophore of the naturally occurring antitumor antibiotics. The relationship of these observations to a chemical mechanism of cellular toxicity is discussed.