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

Abstract

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.

New Acetylenic Amine Derivatives of 5,8-Quinolinediones: Synthesis, Crystal Structure and Antiproliferative Activity

“…The 5,8-quinolinedione derivatives were among the first compounds to be systematically modified in order to find products with higher biological activities, such as anticancer, anti-inflammatory or antibacterial [1][2][3][4][5][6][7][8][9]. For example, it was found that substitution of the electron-withdrawing groups at the 6-or 7-positions of the 5,8-quinolinedione led to an increase in the DNA degradation [8][9][10][11][12][13].…”

Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

“…Метиленовый синий (известный ингибитор NO-зависимой активации растворимой гуанилатциклазы) также тормозит рост лейкемических клеток L 1210 и Р388. Ранее было показано, что противоопухолевый антибиотик стрептонигрин (брунеомицин) тормозит рост лейкемических клеток L1210 [56,57]. Биохимический механизм фармакологического действия стрептонигрина исследовался детально только с точки зрения его влияния на нуклеиновые кислоты.…”

Novel, simple method for the preparation of 7-hydroxy-4-phenylquinoline-2-carboxylic acid

“…Derivatives of quinoline-2-carboxylic (quinaldic) acid [1] are used as model structures of natural antibiotics [2] and biologically active protein molecules [3] and appear in the composition of triostin [4] and saframycin A [5]. The quinaldic acid structural unit is found in Ephedra sp.…”