DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.
Eight substituted phenacyl anthranilates have been prepared by reaction of sodium anthranilate with substituted phenacyl halides in dimethylformamide in the yields from 31 to 93%. The phenacyl esters were cyclized in polyphosphoric acid or by mere heating to give the respective substituted 2-aryl-3-hydroxyquinolin-4(1H)-ones in the yields from 77 to 98%. All the compounds prepared have been characterized by their 1 H and 13 C NMR spectra.Phenacyl bromides belong among very reactive substances and their reaction with sodium salts of lower organic acids giving the corresponding phenacyl esters is well known and has been employed for identification of these acids 1,2 . The direct reaction of anthranilic acid with bromomethyl phenyl ketone has also been described 2,3 . In boiling ethanol in the absence of base, alkylation at amino group predominated to give N-phenacylanthranilic acid 3 . In the presence of base, phenacyl N-phenacylanthranilate was formed 2,3 . Phenacyl anthranilates were prepared by reactions of 2-nitrobenzoic acid with bromomethyl aryl ketones and subsequent reduction of the phenacyl 2-nitrobenzoates formed with hydrogen on palladium 4,5 . The rates of reactions of bromomethyl aryl ketones with nucleophiles are strongly affected by the solvent used. If amides are used as the reaction medium, the reaction is smooth even at room temperature and is exothermic 6 . When these conditions were adopted for the reactions of bromomethyl phenyl ketones I with salts of anthranilic acid, the alkylation predominantly took place at the oxygen atom to give phenacyl anthranilates II mostly in high yields (Scheme 1). The substances prepared were identified by their 1 H and 13 C NMR spectra (Tables I and II). Although quinolines represent an extensively studied class of heterocyclic compounds, only few basic representatives of 2-aryl-3-hydroxyquinolin-4(1H)-ones have been described in literature. The described method of preparation starting from the 2-nitrophenylethylene oxide prepared by the Darzens reaction 7,8 is laborious and the yields of whole synthesis are low. The method given by us for preparation of 3-hydroxyquinolin-4(1H)-ones III was discovered during cyclizations of phenacyl anthranilates (Scheme 1). Literature 4,5 describes their cyclizations in polyphosphoric acid to give the respective 2-aryl-3H-benz[e][1,4]oxazepin-5-ones IV which are converted into the more stable Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
2-Phenyl-3-hydroxy-4(1H)-quinolinones can be considered as aza-analogues of flavones, compounds which are known for the wide-range of their biological activity. These quinolinones were studied as inhibitors of topoisomerase, gyrase and IMPDH. They were tested for anticancer activity in-vitro and were also shown to possess immunosuppressive properties. This review is the first summarizing the synthesis and activity of the mentioned quinolinones.
Synthesis of 1,2‐disubstituted‐3‐hydroxy‐4(1H)‐quinolinones by the cyclization of N‐substituted phenacyl or acetonyl anthranilates is described. Two methods were employed for cyclization of anthranilates. Heating in polyphosphoric acid has a wide scope of applicability. The thermal cyclization in boiling N‐methylpyrrolidone is limited by steric effect.
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