Synthesis and Cytotoxic Activity of Dihydroquercetin Aryl Derivatives

Abstract

Mixed acyl dihydroquercetin derivatives were synthesized for the first time. The cytotoxicity of the acylation products of this flavonoid was determined against cultures of HeLa tumor cells and murine fibroblasts.Novel dihydroquercetin (DHQ, taxifolin) derivatives are currently being synthesized and studied in the search for effective drugs based on flavonoids [1,2]. Earlier, we modified DHQ by esterifying it totally with several pharmacologically active aromatic and aliphatic carboxylic acid chlorides, e.g., benzoic, p-nitrobenzoic, acetylsalicylic, phenylacetic, palmitic, and nicotinic. Peracyl DHQ derivatives were obtained by treating it with these acid chlorides in a 1:5 ratio with a 10% excess at room temperature or with gentle heating at 50 -60°C. The yields of the compounds varied from 65% to 85% depending on the acid [3]. As it turned out, the spectrum of biological activity broadened considerably after introducing the acyls into DHQ [4]. Biological tests confirmed this. It was found that pentanicotinoyl DHQ had the strongest and most varied medical activity [5]. Therefore, we continued the study of acylation of DHQ and its derivative 4,7,3¢,4¢-tetraacetyldihydroquercetin by chlorides of other biologically important carboxylic acids containing heterocycles. We found that the reaction of DHQ with chlorides of thiophenecarboxylic, furancarboxylic, and chlorophenylisoxazolecarboxylic acids under the aforementioned conditions formed novel pentaacyl DHQ derivatives (Fig. 1, I, II, and III) [6].3¢,4¢,3,5,7-Penta-O-(2-chloronicotinoyl)-2,3-dihydroque rcetin (IV) was also synthesized for the first time (Fig. 1). Compound IV was synthesized at room temperature in anhydrous dioxane in the presence of Py as a catalyst and acceptor of released HCl. The structure of IV was confirmed by PMR and 13 C NMR spectroscopic data.It was shown that resonances of all DHQ OH groups disappeared and that new resonances belonging to the heterocycle appeared in the PMR spectrum of IV. In addition, DHQ derivatives with various acyl substituents on the 4,7,3¢,4¢-tetraacetyldihydroquercetin core with a free 5-OH were synthesized. The acylating agents were chlorides of 2-chloronicotinic acid, 3-(2-chlorophenyl-5-methylisoxazole-4-carboxylic acid, furan-2-carboxylic acid, and thiophene-2-carboxylic acid (Fig. 2).Thus, 5-[3-(2-chlorophenyl)-4-isoxazolyl-5-methyl]-3,7,3¢,4¢-tetra-O-acetyl-2,3-dihydroquercetin (V); 5-(2-furanyl)-3,7,3¢,4¢-tetra-O-acetyl-2,3-dihydroquercetin (VI); 5-(2-thiophenyl)-3,7,3¢,4¢-tetra-O-acetyl-2,3-dihydroquercetin (VII); and 5-(2-chloronicotinoyl)-3,7,3¢,4¢-tetra-O-acetyl-2,3-dihydroquercetin (VIII) were synthesized for the first time and were totally acylated DHQ derivatives that contained two different acyl moieties. The structures of VI-VIII were proved using PMR and 13 C NMR methods. Such an approach could expand considerably the spectrum of biological activity of DHQ derivatives.Herein the effect of totally substituted DHQ derivatives on the viability of tumor and normal cells was investigated. The newly synt...

Modification of polyprenol by phosphorylation and acylation

“…[4]. Introduction of the above listed carbocxylic acid residues into dihydroquercetin and cyclodextrin molecules has recently been reported [5][6][7][8] to considerably enhance the biological activity. We anticipated that acylation of polyprenol with aromatic and heterocyclic carboxylic acid chlorides will give rise to potential biologically active nanostructures.…”