Synthesis of 7-( N -12-Cytisinylpropoxy)Isoflavones
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SYNTHESIS OF 7-(N-12-CYTISINYLPROPOXY)ISOFLAVONES
S. P. Bondarenko,1* O. G. Makarenko,1 V. I. Vinogradova,2 and M. S. Frasinyuk1,3
The reactions of cytisine with isoflavone glycidyl ethers were investigated. A series of cytisine–isoflavone conjugates were regioselectively synthesized via opening the oxirane ring by cytisine. Keywords: cytisine, isoflavone, propanolamine, glycidyl ether. The alkaloid cytisine possesses high affinity for nicotinic acetylcholine receptors (nAChRs), especially the neuronal α4β2 subtype [1, 2]. Also, cytisine and its derivatives exhibit antidepressant, neuroprotective, nootropic, antiviral, antiparasitic, insecticidal, and anticancer activity [3]. Cytisine is a promising platform for discovering new compounds with potential therapeutic applications. One of the key directions of cytisine chemistry is the synthesis of 12-N-alkyl derivatives [4–15]. This structural modification can expand the spectrum of pharmacological action of cytisine derivatives and produce compounds affecting H-choline receptors and possessing spasmolytic, hemostatic [6], and antileishmanial properties [9] and antiarrhythmic, analgesic [15], and antineoplastic activity [16, 17]. The present research was aimed at developing a novel efficient method for conjugation of cytisine and isoflavone fragments through an alkoxy linker. The potential of this type of cytisine conjugation for designing biologically active molecules was confirmed by our previous research that found compounds affecting carcinogenesis and revealing their mechanism of action among cytisine–isoflavone conjugates [17]. The phenolic compounds for conjugation to cytisine that were used to develop the method for synthesizing 7-(N-12-cytisinylpropoxy)isoflavones were 7-O-glycidyl ethers of 4′-chloroisoflavone 1a,b [17]; the natural isoflavones formononetin (1c), 2-methylformononetin (1d), cladrin (1e), afromosin (1f), cladrastin (1g), pseudobaptigenin (1h); and isoflavones 1i,j. The isoflavone glycidyl ethers were synthesized via alkylation of the phenol hydroxyl by epichlorohydrin without involving the oxirane ring in the reaction in dimethylacetamide (DMA) in the presence of potash by using an excess of epichlorohydrin [18]. 1
O
O O
O
O 1a-j
13
10
R1 R3
R2
N
a
OH O
N 11
14
O
R3
R2 O
R4
R1
16
2a-j
R4
a: R1 = R2 = R3 = H, R4 = Cl; b: R1 = Me, R2 = R3 = H, R4 = Cl; c: R1 = R2 = R3 = H, R4 = OMe; d: R1 = Me, R2 = R3 = H, R4 = OMe e: R1 = R2 = H, R3 = R4 = OMe; f: R1 = R3 = H, R2 = R4 = OMe; g: R1 = H, R2 = R3 = R4 = OMe; h: R1 = R2 = H, R3R4 = OCH2O i: R1 = R2 = R3 = H, R4 = F; j: R1 = R2 = H, R3R4 = 3′-OCH2CH2O-4′ a. Cytisine, MeCN, (C4H9)4N+I–
1) National University of Food Technologies, 68 Vladimirskaya St., Kiev, 01601 Ukraine, e-mail: [email protected]; 2) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent; 3) V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murmanskaya St., Kiev, 02094 Uk
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