Various conjugates of amino acids with chrysin in which the amino acid was bonded through the C-or N-terminus to the flavone were prepared using peptide chemistry methods (symmetric anhydrides and activated esters).Flavonoids are the most widely distributed compounds of natural origin. They can be found in practically all plant species. At present, flavonoids comprise about 6500 natural compounds [1]. The study of flavonoids is becoming increasingly interesting because of the important role that they play in the metabolism of plants and animals and their high and diversified biological activity [2]. Chrysin (5,7-dihydroxyflavone) is one of the most common flavonoids, has been isolated from various plant families [3,4], and possesses, like its derivatives, a broad spectrum of biological activity. Thus, chrysin exhibits anticancer [5,6], antioxidant [7, 8], anti-inflammatory [9, 10], vasodilating [11, 12], immunomodulating [13, 14], antibacterial [15, 16], antifungal [16], antiprotozal [17], neuroprotective [18], hypotensive [19], and anti-allergy [20] activity. Chrysin derivatives possess hypoglycemic [21], anticancer [22-25], anti-inflammatory [26, 27], and antibacterial [15] action.Considering the importance to the metabolism of all animals of amino acids and their derivatives, our goal was to synthesize chrysin derivatives with pharmacophores containing amino acids.The amino-acid derivatives of chrysin were synthesized via two modification pathways. The first was based on formation of the ester of N-protected amino acid and phenolic compounds. The most suitable and convenient method for synthesizing 7-O-amino-acid chromone derivatives is the reaction of 7-hydroxychromones and symmetric anhydrides of N-substituted amino acids because the reaction proceeds under mild conditions and is not complicated by side reactions [28]. It has been used successfully to synthesize similar types of compounds [29,30].The hydroxyls of 5,7-dihydroxychromones have different reactivities because of the different influence of electrondonors, steric factors, and intramolecular H-bonds. Therefore, the 7-hydroxyl of the chromone system is acylated exclusively under mild conditions [31,32].Symmetric anhydrides of N-protected amino acids were prepared by reaction of dicyclohexylcarbodiimide (DCC) with two equivalents of the corresponding N-protected amino acid in anhydrous dioxane at 0°C. The amines of the amino acids were blocked with t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and p-toluenesulfonic acid (Tos). Chrysin was acylated by the resulting amino-acid anhydrides at 0°C in anhydrous dioxane in the presence of catalytic amounts of 4-dimethylaminopyridine (DMAP) to produce N-protected 7-O-aminoacyl-5-hydroxy-2-phenylchromen-4-ones 2-20. The products contained glycine (2, 8), L-alanine (3, 9), L-valine (4, 10), L-leucine (5, 11), L-isoleucine (6, 12), L-methionine (13), L-phenylalanine (7, 14), β-alanine (15, 17, 19), and 6-aminohexanoic acid (16, 18, 20).The selective acylation of the chromone 7-hydroxyl was confirmed by PMR ...
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Cytisine derivatives modified by furocoumarins were synthesized using activated esters.Many important natural compounds are based on the furocoumarin structure [1]. Highly active pharmacological compounds are known among natural and synthetic furocoumarins [2].On the other hand, the alkaloid cytisine and its derivatives possess a broad spectrum of biological activity [3,4]. Therefore, a large number of publications on the chemical modification and study of the properties of cytisine have appeared [5][6][7][8]. Thus, addition to cytisine of a furocoumarin ring as a substituent is interesting both to the chemistry of alkaloids and coumarins and to the targeted search for new biologically active compounds.Starting furocoumarins 1-12 that contain a carboxylic acid were prepared by the MacLeod method [9, 10]. Cytisine was N-acylated using activated esters [11], a method that is widely employed in peptide synthesis. The carboxylic acid was activated as the highly reactive N-hydroxysuccinimide ester [12]. Activated esters were prepared by reacting the corresponding acids 1-12 and N-hydroxysuccinimide (SuOH) in absolute dioxane using diisopropylcarbodiimide (DIC) as the condensing agent. Condensation of the resulting activated esters with cytisine in dioxane at room temperature gives in high yields the N-acyl cytisine derivatives 13-24, the molecules of which contain furocoumarin moieties. 1, 13: R 1 = Me, R 2 = R 3 = H, n = 1; 2, 14: R 1 = R 3 = Me, R 2 = H, n = 1; 3, 15: R 1 = R 2 = Me, R 3 = H, n = 1; 4, 16: R 1 = R 2 = R 3 = Me, n = 1; 5,17: R 1 R 2 = (CH 2 ) 4 , R 3 = H, n = 1; 6, 18: R 1 R 2 = (CH 2 ) 4 , R 3 = Me, n = 1; 7, 19: R 1 = Me, R 2 = R 3 = H, n = 2; 8, 20: R 1 = R 3 = Me, R 2 = H, n = 2; 9, 21: R 1 = R 2 = Me, R 3 = H, n = 2; 10, 22: R 1 = R 2 = R 3 = Me, n = 2; 11, 23: R 1 R 2 = (CH 2 ) 4 , R 3 = H, n = 2; 12, 24: R 1 R 2 = (CH 2 ) 4 , R 3 = Me, n = 2 C 30 H 30 N 2 O 5 , mp 287-289°C. PMR spectrum (300 MHz, DMSO-d 6 , δ, ppm, J/Hz): 1.84 (2H, m, CH 2 -7″), 1.93 (2H, m, CH 2
Angular dihydropyranocoumarins containing natural and synthetic amino acids and dipeptides were synthesized using activated esters.The benzopyran-2-one system is found in the molecular structures of many important natural compounds [1] and substances with potent pharmacological activities [2]. Adding into the coumarin system a substituent of an amino acid or peptide is interesting to the chemistry of both coumarins and amino acids and for targeted synthesis of new biologically active compounds. Therefore, we functionalized benzopyran bioregulators by adding to them pharmacophoric amino acids and peptides.The 5,7-dihydroxy-2,2-dimethyl-4-chromanone (1) that was necessary for further transformations was prepared by Friedel-Krafts acylation of phluoroglucinol with 3,3-dimethylacrylic acid in the presence of BF 3 etherate [3,4]. Selective alkylation of the 7-phenol [the 5-hydroxy of 1 is bound to the ketone by an intramolecular H-bond (IHB)] using the Williamson reaction and ethylbromoacetate produced ethyl-(5-hydroxy-2,2-dimethyl-4-oxochroman-7-yloxy)acetate (2). The PMR spectrum of 2 contained signals characteristic of the chroman-4-one ring and an ester in addition to a broad singlet at 12.00 ppm that belonged to the free 5-hydroxyl bound through an IHB. Treatment of 2 with FeCl 3 in ethanol (1%) gave a deep brown color due to the formation of an intramolecular chelate complex. Clemensen reduction of 2 using Zn dust in HCl produced ethyl-(5-hydroxy-2,2-dimethylchroman-7-yloxy)acetate (3). The PMR spectrum of 3 has characteristic signals for the 2,2-dimethylchromane rine (6H singlet at 1.22 ppm and two triplets at 1.67 and 2.54 ppm with SSCC 7.2 Hz) and an ester in addition to a broad singlet for the 5-hydroxyl at 9.40 ppm.Pechmann condensation of 3 and ethylacetoacetate in the presence of conc. H 2 SO 4 produced ethyl-(4,8,8-trimethyl-2-oxo-9,10-dihydropyrano-[2,3-f]chromen-5-yloxy)acetate (4). The PMR of this compound contained a simpler splitting pattern for the aromatic protons than that of the starting 2,2-dimethylchromane owing to the decoupling of pyran H-6, as a result of which H-6 of the 8,8-dimethyl-9,10-dihydropyrano[2,3-f]chromen-2-one system was observed as a singlet at 6.26 ppm. The PMR spectrum also contained a singlet at 5.93 ppm that was unambiguously assigned to H-3 and is a characteristic signal of a 4-substituted coumarin ring. Furthermore, the PMR spectrum of 4 exhibited signals typical of a 2,2-dimethyldihydropyran ring and an ester.Alkaline hydrolysis of 4 produced (4,8,8-trimethyl-2-oxo-9,10-dihydropyrano[2,3-f]chromen-5-yloxy)acetic acid (5). Amino-acid derivatives of 5, which has a free carboxylic acid, were synthesized using the activated-ester method that is widely used in peptide synthesis [5]. The carboxylic acid was functionalized using N-hydroxysuccinimide to form the highly reactive ester that does not racemize the synthesis products [6] and has been used successfully to synthesis a similar series of compounds [7,8].
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