Group of synthesis and study of flavonoids properties, Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Compounds

Head of group Mikhailo Frasinyuk, Ph.D.

List of Publications:

1. Development of 6H-Chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues

M. Frasinyuk, S. Bondarenko, V. Sviripa, R. Burikhanov, V. Rangnekar, Chunming Liu, and D Watt

Nitrosation and cyclization of 4-(3-aminothieno[2,3-b]pyridine-2-yl)-2H-chromen-2-ones 1 afforded substituted 6H-Chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones 2 that inhibited the intermediary filament protein, vimentin, at low micromolar concentrations. This inhibition promoted the secretion of Prostate Apoptosis Response-4 protein (Par-4), which selectively triggered apoptosis in prostate cancer cells such as CWR22Rv1, LNCaP-derivative C4-2B, PC-3 and its aggressive analog, PC-3 MM2.

2. AMINOMETHYLATION OF RELATED NATURAL AURONES

A. Popova, S. Bondarenko, G. Mrug, M. Frasinyuk

The aim of our work was development of new pathways for the synthesis of related natural aurones aminomethyl derivatives, which are containing the residues of secondary and tertiary amines.
The well-known method of synthesis of the Mannich bases using the secondary amine and formaldehyde in the presence of catalyst was tested. However, it gave poor chemical yield of aurone Mannich bases which are containing the residues of tertiatry aliphatic, aromatic and heterocyclic amines (написано выше) [1]. The good yield for compounds 2 were obtained by heating of 6-hydroxyaurones 1 with aminals in isopropanol. This procedure allows us to carry out regiospecific aminomethylation of aurones with formation of 7-aminomethyl derivatives 2 exclusively.

3. Synthesis of 8-hydroxymethyl and 8-alkoxymethyl 7-hydroxyisoflavone derivatives

G. Mrug, M. Frasinyuk, V. Khilya

Interaction of natural isoflavone Mannich bases with acetic anhydride were synthesized 7-acetoxy-8-acetoxymethyl isoflavones. Alcoholysis of the diacetoxy isoflavones lead to the formation of 8-alkoxymethyl-7-hydroxy isoflavones instead expected 7-hydroxy-8-hydroxymethyl isoflavones. The last compounds were synthesized under hydrolysis of diacetates in dioxane-water medium at the presence of mineral acid.

4. Aminomethylation Of Isoflavones With Cyclic Amino Alcohols

G. P. Mrug, M. S. Frasinyuk, S. P. Bondarenko, V. S. Brovarets, V.P. Khilya

The analogues of chromone alkaloids were synthesized by aminomethylation of natural isoflavones such as formononetin, 2 methylformononetin, cladrin, 7-hydroxy-2-methyl-3-phenylchromone and 2-methyl cladrin derivative with (S)-prolinol, trans-4-hydroxy-L-proline and 3-hydroxypiperidine.

5. Synthesis and Tautomerization of Hydroxylated Isoflavones Bearing Heterocyclic Hemi-Aminals

M. Frasinyuk, S. Bondarenko, V. Khilya, Chunming Liu, D. Watta, and V. Sviripa

The aminomethylation of hydroxylated isoflavones with 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol, and 5-amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-hydroalkyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-4-ones 4 and/or the tautomeric 7-hydroxy-8-(1,3-oxazepan-3-ylmethyl)-4H-chromen-4-ones 5. The ratio of these tautomers was dependent on solvent polarity, electronic effects of aryl substituents in the isoflavone and the structure of the amino alcohol. NMR studies confirmed the interconversion of tautomeric forms.

6. Feature of aminomethylation of esculetin derivatives

M. Frasinyuk

4-Subsituted esculetine derivatives were synthesized by condensation of pyrogalol A ethyl acetoacetate or ethyl 4-chloroacetoacetate under Pechmann's reaction. 4-Hydroxymethylesculetin was synthesized by acetylation of 4-chloromethylesculetin with acetic anhydride in presence of potassium acetate and subsequent deacylation in ethanol. Aminomethylation of 4-methyl- and 4-hydroxymethyl esculetin derivatives was studied at various reaction conditions. A different 8-aminomethyl esculetine derivatives and 2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones were synthesized with good or excellent yield.

7. ALKALOID-FLAVONOID CONJUGATES

S. Bondarenko, V. Khilya, A. Popova, M. Frasinyuk

The interaction of 7-isoflavonoids with alkaloids in Mannich reaction was studied for the synthesis of semi-synthetic related alkaloid-flavonoid conjugates. The possibility of applying of cytisine, anabasine, and aloperine as amine was shown for aminomethylation of 7-hydroxyisoflavones, 6-hydroxyaurones, and related 6-hydroxy-3-hetarylbenzofuran-3-ones with paraformaldehyde. In all cases using of 4-(dimetylamino)pyridine was required. The aminomethylation of 7-hydroxyisoflavones with alkaloids was regioselective and led to formation of 8-alkaloid-methyl-7-hydroxyisoflavones. The similar reaction with 6-hydroxyaurones and their hetero analogues led to 7-aminomethyl substituted benzylideno 6-benzofuran-3-ones.
Another way for the synthesis of alkaloid-isoflavone conjugates was alkylation of cytisine or aloperine with 7-(2-bromoethoxy)isoflavones, which were obtained by alkylation with 1,2-dibromoethane. In this cases C2-linked hybrids were obtained.
Thus, we synthesized various derivatives containing flavonoid and cytisine, aloperin, or anabasine moieties connected by one or two methylene groups in the position 8 or in O-7 of the chromone ring respectively. Another type of alkaloid-flavonoid conjugates are presented as 7-aminomethyl-6-hydroxyaurones.

8. REGIOSPECIFIC SYNTHESIS OF 4,5-DIARYLISOXAZOLES BEARING CYTISINE MOIETY

S. Bondarenko, M. Frasinyuk, V. Khily, V. Vinogradova

Thus, reaction of hydroxylamine hydrochroride with compounds 2 (R1 = Me) in pyridine led to formation only 2-methyl-3-aryl-4-(4-(2-(cytisin-12yl)ethoxy-2-hydroxyphenyl))isoxazoles 3.
In case of 2-terminated isoflavones 2 the similar reaction led to formation of both regio-isomeric isoxazoles. It was found, the formation of target regio-isomeric isoxazoles 3 (R1 = H) is possible in ethanol in presense of 4-methylmorpholine, which provide nucleophile attack in C-2 chromone ring.
The structures of 4,5-diarylisoxazoles 3 were confirmed by HSQC and HMBC spectra. In case of 2-methyl isoxazole derivatives with HMBC spectra were identified that 2-Me group is linked with carbon at 158-160 ppm, and carbon at 163-165 ppm is linked with phenolic substituent. The similar results were observed for compounds 3 (R1 = H). It was identified with HSQC spectra, CH carbon shift was 151-152 ppm. These data are confirming regiospecific formation 4,5-diarylisoxazoles 3.

9. APPLYING OF 4-CHLOROMETHYLCOUMARINS AS SYNTHONES FOR THE SYNTHESIS OF FUSED HETEROCYCLIC SYSTEMS

S.P. Bondarenko, M.S. Frasinyuk

We developed new methods for the synthesis of various fused coumarins using 4-chloromethylcoumarins as versatile starting compounds. Alkylation of 2-cyanophenol with 4-chloromethylcoumarins led to one-pot formation of 4-(3-aminobenzofuran-2-yl)coumarins 3 via formation of 4-aryloxymethylcoumarins 2 and intramolecular cyclization cyano and active methylene groups. The similar reaction involving 2-mercapto-3-cyanopyridines required alkylation in EtOH with presence of organic base and isolation of S-alkylpyridines 4. 4-(3-Aminothieno[2,3-b]pyridin-2-yl)-2H-chromen-2-ones (5) were synthesized by subsequent cyclization compounds 4 in DMF with presence of K2CO3 as base (scheme 1).

Unusual condensation of compounds 3,5 with aldehydes led to formation of fused pyridino[3,4-c]coumarins 10, 11 which is results of formation of the Shiff's bases 6,7, intramolecular [5+1] cycloaddition and oxidation of dihydropyridino[3,4-c]coumarins 8, 9 [2,3].
Interaction of compounds 5 with BuONO in formic acid led to synthesis of diazo compounds 12 with further intramolecular ring-closure reaction and formation of 6H-chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones 13 [4] (scheme 2).

Список останніх публікацій

1. M. S. Frasinyuk, G. P. Mrug, S. P. Bondarenko, V. M. Sviripa, W. Zhang, X. Cai, M. V. Fiandalo, J. L. Mohler, C. Liu, D. S. Watt, Application of Mannich Bases to the Synthesis of Hydroxymethylated Isoflavonoids As Potential Antineoplastic Agents, Org. Biomol. Chem., 2015, 13 (46), 12292-11301. http://dx.doi.org/10.1039/C5OB01828E

2. М. С. Фрасинюк, Особливості амінометилювання похідних ескулетину, Ukr. Вioorg. Acta, 2015, 13 (1), 3 - 8.

3. M. S. Frasinyuk, S. P. Bondarenko, V. M. Sviripa, R. Burikhanov, V. M. Rangnekar, C. Liu, D. S. Watt, Development of 6H-Chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues, Tetrahedron Lett., 2015, 56, 23, 3382 - 3384. http://dx.doi.org/10.1016/j.tetlet.2015.01.028

4. S. P. Bondarenko, М. S. Frasinyuk, V. P. Khilya, Synthesis of aloperine-containing Mannich bases of isoflavones, Chem. Nat. Compd., 2014, 51 (4), 643 - 645. http://dx.doi.org/10.1007/s10600-015-1375-8

5. T. V. Shokol, N. V. Gorbulenko, M. S. Frasinyuk, V. P. Khilya, Synthesis of 6-(3-Pyrazolyl)-4-Methylumbelliferone Derivatives Substituted on the Pyrazole Ring, Chem. Nat. Compd., 2014, 51 (4), 630 - 633. http://dx.doi.org/10.1007/s10600-015-1371-z

6. M. S. Frasinyuk, S. P. Bondarenko, V. P. Khilya, C. Liu, D. S. Watt, V. M. Sviripa, Synthesis and Tautomerization of Hydroxylated Isoflavones Bearing Heterocyclic Hemi-Aminals, Org. Biomol. Chem., 2015, 13 (4), 1053-1067. http://dx.doi.org/10.1039/c4ob02137a

7. І. С. Безверха, Т. М. Пантелеймонова, М. У. Заїка, Л. Б. Шарабура, М. С. Фрасинюк, В. П. Хиля, Антидепресивна дія ізофлавону 5/09 при тривожній депресії у самців мишей, Пробл. Старения и долголетия, 2014, № 2, 101-112.

8. Патент №105959, Україна, МПК (2014.01) С07D311/36, A61/K 31/00, C07D 295/04. 7-[2-(4-Етилпіперазин-1-іл)етокси]-2-метил-3-(4-хлорофеніл)-4Н-хромен-4-он та його застосування / І. С. Безверха, С. П. Бондаренко, М. У. Заїка, Т. М. Пантелеймонова, М. С. Фрасинюк, В. П. Хиля, Л. Б. Шарабура; патентовласник ДУ "Інститут геронтології ім. Д. Ф. Чеботарьова НАМНУ" - заявка № а20123435; заявл. 26.11.2012; опублік. 26.05.2014, Бюл. № 10.

9. G. P. Mrug, M. S. Frasinyuk, S. P. Bondarenko, V. S. Brovarets, V. P. Khilya, Aminomethylation of isoflavones with cyclic amino alcohols, Ukr. Вioorg. Acta, 2014, 12 (2), 10 - 14. http://www.bioorganica.org.ua/UBAdenovo/vol_12_2.htm

10. G. P. Mrug, M. S. Frasinyuk, V. P. Khilya, Synthesis of 8-hydroxymethyl and 8-alkoxymethyl 7-hydroxyisoflavone derivatives, Ukr. Вioorg. Acta, 2014, 12 (1), 24 - 28. http://www.bioorganica.org.ua/UBAdenovo/vol_12_1.htm

11. M. S. Frasinyuk, Synthesis and aminomethylation of 3-substituted 6-hydroxy-1,2-benzisoxazoles, Chem. Heterocycl. Compd., 2014, 50 (11), 1616-1623. http://dx.doi.org/10.1007/s10593-014-1631-z

12. S. P. Bondarenko, М. S. Frasinyuk, V. I. Vinogradova, V. P. Khilya, Synthesis of 4-aryl-3-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]pyrazoles, Chem. Nat. Compd., 2014, 50 (5), 889-891. http://dx.doi.org/10.1007/s10600-014-1107-5

13. M. S. Frasinyuk, S. Kwiatkowski, J. M. Wagner, T. J. Evans, R. W. Reed, K. V. Korotkov, D. S. Watt, Pentapeptide Boronic Acid Inhibitor of Mycobacterium tuberculosis MycP1 Protease, Bioorg. Med. Chem. Lett., 2014, 24 (15), 3546-3548. http://dx.doi.org/10.1016/j.bmcl.2014.05.056

14. А. Hamza, J. M. Wagner, T. J. Evans, M. S. Frasinyuk, S. Kwiatkowski, C.-G. Zhan, D. S. Watt, K. V. Korotkov, Novel Mycosin Protease MycP1 Inhibitors Identified by Virtual Screening and 4D Fingerprints, J. Chem. Inf. Model., 2014, 54 (4), 1166 - 1173. http://dx.doi.org/10.1021/ci500025r

15. M. S. Frasinyuk, S. P. Bondarenko, N. V. Gorbulenko, A. V. Turov, V. P. Khilya, Cyclic carboxylic anhydrides as new reagents for formation of chromone ring, J. Heterocycl. Chem., 2014, 51, 768 - 774. http://dx.doi.org/10.1002/jhet.1721

16. S. P. Bondarenko, E.V. Podobii, М. S. Frasinyuk, V. I. Vinogradova, V. P. Khilya, Synthesis of Cytisine Derivatives of Flavonoids. 4. Synthesis of 3-aryl-7-[2-(cytisin-12-yl)ethoxy]coumarins. Chem. Nat. Compd., 2014, 50, 420 - 423. http//dx.doi.org/10.1007/s10600-014-0975-z

17. M. S. Frasinyuk, G. P. Mrug, S. P. Bondarenko, V. P. Khilya, V. S. Brovarets, Antitumor activity of flavonoid Mannich bases, Ukrainica Bioorganica Acta, 2013, 11, 2, 3-7 (Ukr).http://www.bioorganica.org.ua/UBAdenovo/vol_11_2.htm

18. S. P. Bondarenko, M. S. Frasinyuk, Synhsis of aminomethyl derivatives of chrysin, Chem. Nat. Compd., 2013, 49, 841 - 844. http://dx.doi.org/10.1007/s10600-013-0760-4

19. S. P. Bondarenko, O. N. Miroshnikov, M. S. Frasinyuk, V. P. Khilya, Synthesis of 4-aryl-5-[2-hydroxy-4-?-(N,N-dialkylamino)ethoxyphenyl]isoxazoles, Chem. Nat. Compd., 2013, 49, 826 - 829. http://doi.org/10.1007/s10600-013-0757-z

20. I. S. Bezverha, T. M. Panteleymonova, M. U. Zaika, L. B. Sharabura, М. S. Frasinyuk, V. P. Khilya, S. P. Bondarenko, Antidepressant and neuroleptic action of new derivatives nitrogen-containing isoflavones, Problemy stareniy i dolgoletiya, 2013, 22, 2, 145 - 155 (Ukr).

21. G. P. Mrug, S. P. Bondarenko, V. P. Khilya, M. S. Frasinyuk, Synthesis and aminomethylation of 7-hydroxy-5-methoxyisoflavones, Chem. Nat. Compd., 2013, 49, 235 - 241. http://dx.doi.org/10.1007/s10600-013-0570-8

22. S. P. Bondarenko, М. S. Frasinyuk, V. I. Vinogradova, V. P. Khilya, Synthesis of Cytisine Derivatives of Flavonoids. 3. Synthesis of 7-[2-(cytisin-12-yl)ethoxy]isoflavones. Chem. Nat. Compd., 2012, 48, 970 - 973. http://dx.doi.org/10.1007/s10600-013-0441-3

23. S. P. Bondarenko, М. S. Frasinyuk, V. P. Khilya, T. M. Panteleymonova, I. S. Bezverkha, Synthesis and antioxidant activity of 6- and 7-hydroxy-3-arylcoumarins, Ukrainica Bioorganica Acta, 2012, 10, 42 - 47. http://www.bioorganica.org.ua/UBAdenovo/vol_10_1.htm

24. S. V. Gorelov, S. P. Bondarenko, М. S. Frasinyuk, Synthesis and Properties of 4-(3-Aminothieno[2,3-b]pyridin-2-yl)coumarins, Chem. Heterocycl. Compd., 2012, 48, 955-962. http://dx.doi.org/10.1007/s10593-012-1083-2

25. M. S. Frasinyuk, G. P. Mrug, O. D. Fedoryak, S. P. Bondarenko, Synthesis of aminoacyl derivatives of formononetin and cladrin, Chem. Nat. Compd., 2012, 48, 570-573. http://dx.doi.org/10.1007/s10600-012-0313-2.

26. S. P. Bondarenko, М. S. Frasinyuk, A. I. Galayev, V. I. Vinogradova, New flavonoid-contain derivatives of lupinine. Chem. Nat. Compd., 2012, 48, 234-237. http://dx.doi.org/10.1007/s10600-012-0212-6

27. М. S. Frasinyuk, S. P. Bondarenko, V. P. Khilya, Chemistry of 3-Hetarylcoumarins. 3. Synthesis and Aminomethylation of 7'-Hydroxy-3,4'-bicoumarins. Chem. Heterocycl. Compd., 2012, 48, 422- 426. http://dx.doi.org/10.1007/s10593-012-1009-z

28. S. P. Bondarenko, М. S. Frasinyuk, V. P. Khilya, Synthesis of Aminomethyl Derivatives of Sophoricoside. Chem. Nat. Compd., 2012, 48, 26-29. http://dx.doi.org/10.1007/s10600-012-0151-2

29. S. P. Bondarenko, М. S. Frasinyuk, V. I. Vinogradova, V. P. Khilya, Synthesis of Cytisine Derivatives of Flavonoids. 2. Aminomethylation of 7-hydroxyisoflavones. Chem. Nat. Compd., 2011, 47, 604-607. http://dx.doi.org/10.1007/s10600-011-0006-2

30. М. S. Frasinyuk, S. P. Bondarenko, O.V. Shablykina, V. P. Khilya, Formylation of 5-Hydroxybenzofuran Derivatives and Synthesis of Furo[3,2-f]coumarins based them. Chem. Heterocycl. Compd., 2011, 47, 1155- 1163. http://dx.doi.org/10.1007/s10593-011-0886-x

31. S. P. Bondarenko, М. S. Frasinyuk, V. I. Vinogradova, V. P. Khilya, Synthesis of flavonoid derivatives of cytisine. 1. Aminomethylation of 7-hydroxy-3-arylcoumarins. Chem. Nat. Compd., 2010, 46, 771-773. http://dx.doi.org/10.1007/s10600-010-9737-8

32. S. P. Bondarenko, М. S. Frasinyuk, V. P. Khilya, Aminomethylation of 3-Aryl -7-hydroxycoumarins. Chem. Heterocycl. Compd., 2010, 46, 529-535. http://dx.doi.org/10.1007/s10593-010-0541-y

33. S. P. Bondarenko, М. S. Frasinyuk, V. P. Khilya, Features of Aminomethylation of 7-Hydroxy-4'-Fluoroisoflavones with Primary Amines, Chem. Heterocycl. Compd., 2010, 46, 146-150. http://dx.doi.org/10.1007/s10593-010-0485-2