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...
The flavonoid dihydroquercetin and its esterified derivatives possess various biological activities and are widely used as dietary supplements and in pharmacology. A significant disadvantage of this flavonoid is its low solubility in water at ordinary temperatures of up to 0.03%, which negatively affects its biological activity. Nature overcomes this problem by glycosylation, sulfation, and phosphorylation. In chemistry and pharmacology to overcome this problem, there are several synthetic approaches. For dihydroquercetin (DHQ) is the inclusion of DHQ in the cyclodextrin matrix or the formation of a complex of DHQ with basic natural amino acids. In this paper, a method is proposed for obtaining water-soluble morpholinium salts based on chloroacylated derivatives of DHQ. The acylation reaction was carried out in dioxane, pyridine was used as an acceptor of choric hydrogen. The target compounds were obtained with a yield of 68-79%. As a result, chlorinated derivatives based on DHQ and its acyl and benzyl derivatives were synthesized. These derivatives in the interaction with morpholine form its salts, which, as it turned out, have a high water solubility. Pentamorpholine salt of DHQ had the highest solubility in water, up to 6.5% at room temperature, which is 200 times more soluble than the original DHQ. The proposed synthetic approach to increase the water solubility of acyl derivatives of DHQ can be extended using other nitrogenous bases and other haloacyl derivatives of DHQ.
Впервые синтезированные 3-моноацилированные производные дигидрокверцетина обладают антиоксидантной и цитотоксической активностью в отношении опухолевых клеток (линия HeLa).
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