DOI: /jcprm :

Transcription

1 DI: /jcprm : *,.,.,.,. 3,, ( ), mngorb@newmail.ru (Bétula) 2-, c., - N-. MS. :,,. ( ) [1], - [2]. -,, -,,, -,.,, -,. -,,.,,, mngorb@newmail.ru,,,, [3], 2,3- - [4], - [5]. *,.

2 92.,.,.,. [6] 2- - [7] (., (Bétula) [8]. [6], 2- - [9]. 2- [10]. ( ) Alfa Aesar, T. 78 º, n 20 D = 1,3910. N ( ) Lancaster, = 65 º / 1,5., n 20 = 1,5117. D ( ),, r 1 r 2 [11] [12]. 1 Varian Mercury c 300. DCl 3,. 549 ( ), RD ( ) MS ( ) - DMEM ( A549 RD) RPMI 1640 ( MS) 10%, 2 M L- 1% 37 C 5% C 2. MS, (. ) DMEM 10% 0,3% 37 5% 2 C 2 Isotemp Barnstead ( ) , [13] FLUstar PTIMA BMG Labtech GMBH ( )., ,., XX. [14 22].,, %. [22].

3 ( ) 2- ( ) (. 1) ( ) 2- ( ),, -, 2 2 ( P n 3 30) [23, 24] ,. CH 2 CH CH 2 CH CH 2 CH 2 CH 2 CH 2 CH CH CH 2 XR XR CH 2 XR XR CH 2 CH CH XR CH 2 CH CHXR : -, -,. -.,.,.. [23, 25 32].,, ( ),., (CaCl 2, ZnCl 2 ) (HCl, H 3 P 4 ) - n = [33, 34]., ( ) [35]. ( - ). - (,, - ),. - [36, 37], -,.,.

4 94.,.,.,., -, - N-., (. 2). - ( 1 ) 1., -. - (. 3). - (M 2 ), -, ,3 ± 1,5. «-»., -,,, H (. 2) m 2.% 1 3 y = 0,5x - 15 R² = 0, (1, 3) (2, 4) (1, 2) (3, 4). M 2 m ] = 5,7, [ ] = 0,13, T = 80 C. 3. ( 1 ) (1) (2). ] = 3.%, = ( 2 ) (, 80 ) 1 2 r 1 r 2 r 1 r 2 0,12 ± 0,003 4,65 ± 0,20 0,56 0,02 ± 0,001 6,15 ± 0,23 0,12 0,49 ± 0,006 1,48 ± 0,11 0,73 0,35 ± 0,050 1,94 ± 0,10 0,68

5 (DMS) C NH n m 36 CN (CNH), ( ), (CN), (NH). 0,86, 0,92, 0,98, 1,01, 1,14 (15, 5, , 24, 25, 26, 27); 1,28 (2,, 2-34); 1,57 (2,, 2-32); 1,67 (3,, 3-30); 1,83 (2,, 2-33); 2,39 (1,, -35); 3,14 (3,, -19, H-31); 4,58 4,64 (2, 2, 2-29), 7,78 (1,, NH). HN C NH n m 36 CN (CNH, =N), (C=), (CN), (H, NH). 0,78, 0, 92, 0,99, 1,05, 1,08 (15, 5, 5 3 H-23, 24, 25, 26, 27); 1,24 (2,, 2-34); 1,69 (2,, 2-32); 1,71 (3,, 3-30); 1,83 (2,, 2-33); 1,96 2,78 (2, 2, 2-1), 2,11 (1,, -35); 3,21 (3,, -19, H-31), 4,60 4,72 (2, 2, 2-29), 6,68 (1,, NH) C NH n N 36 m (CNH), , ), (NH). 0,85, 0,87, 0,92, 0,97, 1,05 (15, 5, 5 3 H-23, 24, 25, 26, 27); 1,20 (2,, 2-34); 1,36 (2,, 2-32); 1,45 (2,, 2-33); 1,63 (3,, 3-30); 1,79 (2,, 2-38); 2,38 (2,, 2-37); 3,04 (1,, -19); 3,35 (2,, H-31); 3,68 (1,, 2-39); 4,45 (1,, -35); 4,53 4,65 (2, 2, 2-29); 7,79 (1,, NH). HN C NH n N m (CNH, =N), , (C=), (H, NH). 0,90, 0,91, 0,99, 1,07, 1,12 (15, 5, 5 3 H-23, 24, 25, 26, 27); 1,17 (2,, 2-34); 1,30 (2,, 2-32); 1,48 (2,, 2-33); 1,68 (3,, 3-30); 1,96 (2,, 2-38); 2,12 2,91 (2, 2, 2-1); 2,31 (2,, 2-37); 3,25 (3,, - 19, H-31); 3,34 (1,, 2-39); 4,47 (1,, -35); 4,60 4,71 (2, 2, 2-29); 7,85 (1,, NH).. [16, 17, 38 40],, -., -., AA 4 MS - (. 3).

6 96.,.,.,. 3. (. 2), 50% (IC 50 ), S RD A ,84 ± 7,32 44,55 ± 0,25 (2) (4) 40,48 ± 7,19 171,90 ± 1,11 1., N , (, ),. 1. Lee S.M., Min B.S., Lee C.G., Kim K.S., Kho Y.H. Cytotoxic triterpenoids from the fruits of Zizyphus jujuba // Planta Med Vol. 69. N11. Pp olstikova.g., Sorokina I.V., Tolstikov G.., Tolstikov.G., Flekhter.B. Biological activity and pharmacological prospects of lupane terpenoids: II. Semisynthetic lupane derivatives // Rus. J. Bioorg. Chem Vol. 32. N3. Pp Era V., Jaaskelamen P., Ukkonen. Fatty acid ersters from betulinol // J. Amer. il Chem. Soc Vol. 58. N1. Pp Era V., Mustonen., Jaaskelainen. Polyakrylates from betulinol // Mackromol. Chem. Rapid Commun Vol. 2. Pp ( ). - /.,.,. / ,.,.,.,.,.,.,.,.,.,.,. 3- // ( ). -1 /.,.,.,. / ,.,.,.,.,.,.,.,.,.,. -. // ,.,.,.,. - 2,3- // ,.,.,. - // Finemann M., Ross S.D. Linear method for determining monomer reactivity ratios in copolymerization // J. Polym. Sci Vol. 5. Pp Kelen T., Tüd s F. Analysis of the linear methods for determining copolymerization reactivity ratios. I. A new improved linear graphic method // J. Macromol. Sci., Chem Vol. 9. N1. Pp Scudiero D.A., Shoemaker R.H., Paull K.D., Monks A., Tierney S., Notziger T.H., Currens M.T., Seniff D., Boyd M.K. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines // Cancer Res Vol. 48. Pp Ruzicka L. Perspektiven der Biogenese und der Chemie der Terpene // Pure Appl. Chem N6. Pp Hayek., Jordis U., Moche W., Saure F. A bicentennial of betulin // Phytochemistry N28. Pp Ekman R. Lipophilic extractives of the inner bark of birch, Betula verrucosa Ehrh // Finn. Chem. Lett N7 8. Pp Ekman R. The suberin monomers and triterpenoids from the outer bark of Betula verrucosa Ehrh // Holzforschung Vol. 37. N4. Pp Cole B., Bentley M., Hua Y., Bu L. Triterpenoid constituens in the outer bark of Betulaalleghaniensis (yellow birch) // J. Wood Chem. Technol Vol. 11. N2. Pp

7 Seshadri.,Vedantham T. Chemical examination of the barks and heartwoods of betula species of american origin // Phytochemistry Vol. 10. N4. Pp HuaY., Bentley M., Cole B., Murray K., Alford R. Triterpenes from the uter Bark of Betulanigra // J. Wood Chem. Technol Vol. 11. N4. Pp Habiyaremye I., Stevanovic-Janezic B., Garneau F.-X., Riedl B., Jean F.-I. Pentacyclictriterpene constituents of yellow birch (Betulaalleghaniensis) bark from Quebec // J. Wood Chem. Technol Vol. 22. N2. Pp ,. Betula // ,.,..., ,.,. // Zubov V.P., Lachinov M.B., Golubev V.B., Kulikova V.F., Kabanov V.A., Polak L.S., Kargin V.A. The influence of complex agents on the polymerization of vinyl and allyl monomers // J. Polym. Sci. C Vol. 23. N1. p ,.,.,.,..,. - //. A ,.,.,.,.,.,. - // ,.,.,.,.,. - // ,.,.,.,. - // Zubov V.P., Kumar M. Vijaya, Masterova M.N., Kabanov V.A. Reactivity of allyl monomers in radikal polymerization // J. Macromol. Sci Vol. 13. N1. Pp : , Hill D.J.T., Donnell J.J., Sullivan P.W. The role of donor-acceptor complexes in polymerization // Prog. Polym. Sci Vol. 8. N3. Pp ,.,..., ,.,. N- // ,.,. N- - // ,.,. // ,.,.,. - // ,.,.,.,.. // Krasutsky P. A. Birch bark research and development // Nat. prod. rep Vol. 23. N6. Pp Alakurtti S., Mäkelä T., Koskimies S., Yli-Kauhaluoma J. Pharmacological properties of the ubiquitous natural product betulin // Europ. J. Pharm. Sciences Vol. 29. Pp

8 98.,.,.,. Gorbunova M.N. *, Krainova G.F., Tolmacheva I.A., Grishko V.V. SYNTHESIS F NEW BILGICALLY ACTIVE PLYMER BICNJUGATES N THE BASIS F LUPANE ALLYLAMIDES Institute of Technical Chemistry of Ural Branch of RAS, ul. ac. Korolev, 3, Perm, (Russia), mngorb@newmail.ru The work is devoted to the synthesis of new copolymers based on allylamides of betulonic and 2 hydroximinobetulonic acids and study of their cytotoxic activity. Allylamides of betulonic and 2 hydroximinobetulonic acids were prepared by the reaction of corresponding acids with allylamine in the presence of oxalyl chloride and triethylamine. It was established that the allylamides obtained do not homopolymerize, but copolymerize with low rates with acrylonitrile and N-vinylpyrrolidone in the presence of radical initiators The investigations of radical copolymerization of allylamides with acrylonitrile and N-vinylpyrrolidone showed that the resulting copolymers have a statistical distribution of the comonomer units in the macromolecule, wherein in the entire range of monomer concentrations the copolymers are enriched by the vinyl monomer units. The copolymerization rates are considerably reduced by increasing the content of allylamides in the initial monomer mixture in all copolymerization systems, the copolymerization rate of allylamide with acrylonitrile is higher than with N-vinylpyrrolidone. At the copolymerization in bulk with enhancing degree of conversion there is a "gel-effect", which is associated with an increasing of the viscosity in the absence of solvent; at the copolymerization in solution "gel-effect" is absent. The structure of the copolymers obtained was determined by 1 H NMR spectroscopy. It was established that the products obtained are a mixture of copolymers of allyl amides and oligomers thereof. In the spectra of the reaction products a number of additions of the vinyl monomer with the participating of double bond of isopropylidene group is also observed. The copolymers obtained have a cytotoxic activity: the copolymer of allylamide of betulonic acid with N-vinylpyrrolidone exhibits 4-fold higher activity against MS culture when compared with the initial ally amide and is promising for developing new bioactive polymer bioconjugates. Keywords: Lupanova allylamides, radical copolymerization, cytotoxic activity. References 1. Lee S.M., Min B.S., Lee C.G., Kim K.S., Kho Y.H. Planta Med. 2003, vol. 69, no. 11, pp olstikova.g., Sorokina I.V., Tolstikov G.., Tolstikov.G., Flekhter.B. Rus. J. Bioorg. Chem. 2006, vol. 32, no. 3, pp Era V., Jaaskelamen P., Ukkonen. J. Amer. il Chem. Soc. 1981, vol. 58, no. 1, pp Era V., Mustonen., Jaaskelainen. Mackromol. Chem. Rapid Commun. 1981, Vol. 2, pp Patent (SU) (in Russ.). 6. Flehter.B., Ashavina.Ju., Boreko E.I., Karachurina L.T., Pavlova N.I., Kabal'nova N.N., Savinova.V., Galin F.Z., Nikolaeva S.N., Zarudij F.S., Baltina L.A., Tolstikov G.A. Himiko-farmacevticheskij zhurnal, 2002, vol. 36, no. 6, pp (in Russ.). 7. Patent (RU) (in Russ.). 8. Flehter.B., Nigmatullina L.R., Baltina L.A., Karachurina L.T., Galin F.Z., Zarudij F.S., Tolstikov G.A., Boreko E.I., Pavlova N.I., Nikolaeva S.N., Savinova.V. Himiko-farmacevticheskij zhurnal, 2002, vol. 36, no. 9, pp (in Russ.). 9. Tolmacheva I.A., Grishko V.V., Boreko E.I., Savinova.V., Pavlova N.I. Himija prirodnyh soedinenij, 2009, no. 5, pp (in Russ.). 10. Krajnova G.F., Tolmacheva I.A., Gorbunova M.N., Grishko V.V. Himija prirodnyh soedinenij, 2013, no. 2, pp (in Russ.). 11. Finemann M., Ross S.D. J. Polym. Sci. 1950, vol. 5, pp Kelen T., Tüd s F. J. Macromol. Sci., Chem. 1975, vol. 9, no. 1, pp Scudiero D.A., Shoemaker R.H., Paull K.D., Monks A., Tierney S., Notziger T.H., Currens M.T., Seniff D., Boyd M.K. Cancer Res. 1988, vol. 48, pp Ruzicka L. Pure Appl. Chem. 1963, no. 6, pp Hayek., Jordis U., Moche W., Saure F. Phytochemistry, 1989, no. 28, pp Ekman R. Finn. Chem. Lett. 1983, no. 7 8, pp Ekman R. Holzforschung, 1983, vol. 37, no. 4, pp Cole B., Bentley M., Hua Y., Bu L. J. Wood Chem. Technol. 1991, vol. 11, no. 2, pp Seshadri.,Vedantham T. Phytochemistry, 1971, vol. 10, no. 4, pp HuaY., Bentley M., Cole B., Murray K., Alford R. J. Wood Chem. Technol. 1991, vol. 11, no. 4, pp Habiyaremye I., Stevanovic-Janezic B., Garneau F.-X., Riedl B., Jean F.-I. J. Wood Chem. Technol. 2002, vol. 22, no. 2, pp Pohilo N.D., Uvarova N.I. Himija prirodnyh soedinenij, 1988, no. 3, pp (in Russ.). 23. Kabanov V.A., Zubov V.P., Semchikov Ju.D. Komplekso-radikal'naja polimerizacija. [Complexo-radical polymerization]. Moscow, 1987, 256 p. (in Russ.). 24. Volodina V.I., Tarasov A.I., Spasskij S.S. Uspehi himii, 1970, vol. 39, no. 2, pp (in Russ.). 25. Zubov V.P., Lachinov M.B., Golubev V.B., Kulikova V.F., Kabanov V.A., Polak L.S., Kargin V.A. J. Polym. Sci. C. 1968, vol. 23, no. 1, pp Kulikova V.F., Savinova I.F., Zubov V.P., Kabanov V.A., Polak L. S., Kargin V.A. Vysokomolekuljarnye soedinenija. A. 1967, vol. 9, no. 2, pp (in Russ.). * Corresponding author.

9 Kornil'eva V.F., Masterova M.N., Garina E.S., Zubov V.P., Kabanov V.A., Polak L.S., Kargin V.A. Vysokomolekuljarnye soedinenija. A. 1971, vol. 13, no. 8, pp (in Russ.). 28. Zubov V.P., Garina E.S., Kornil'eva V.F., Masterova M.N., Kabanov V.A., Polak L.S. Vysokomolekuljarnye soedinenija. A. 1973, vol. 15, no. 1, pp (in Russ.). 29. Masterova M.N., Andreeva L.I., Zubov V.P., Polak L.S., Kabanov V.A. Vysokomolekuljarnye soedinenija. A. 1976, vol. 18, no. 9, pp (in Russ.). 30. Zubov V.P., Kumar M. Vijaya, Masterova M.N., Kabanov V.A. J. Macromol. Sci , vol. 13, no. 1, pp Zubov V.P. Jeffekty kompleksoobrazovanija v radikal'noj polimerizacii: diss. dokt. him. nauk. [Effects of complexation in radical polymerization: doctor chemical sciences diss.]. Moscow, (in Russ.). 32. Hill D.J.T., Donnell J.J., Sullivan P.W. Prog. Polym. Sci. 1982, vol. 8, no. 3, pp Zubov V.P., Golubev V.B., Stojachenko I.L. Novoe v cheredujushhejsja sopolimerizacii. [New in the alternating copolymerization]. Moscow, 1983, 214 p. (in Russ.). 34. Korshak V.V., Shtil'man M.I., Zalukaeva T.P. Vysokomolekuljarnye soedinenija. B. 1979, vol. 21, no. 12, pp (in Russ.). 35. Panarin E.F., Tarasova N.N., Gorbunova.P. Zhurnal prikladnoj himii. 1993, vol. 66, no. 11, pp (in Russ.). 36. Ageev A.I., Ezrielev A.I., Roskin E.S. Vysokomolekuljarnye soedinenija. A. 1968, vol. 10, no. 11, pp (in Russ.). 37. Ageev A.I., Ezrielev A.I., Mazo L.D., Roskin E.S. Vysokomolekuljarnye soedinenija. A. 1970, vol. 12, no. 9, pp (in Russ.). 38. Tolstikov G.A., Flehter.B., Shul'c Je.Je., Baltina L.A., Tolstikov A.G. Himija v interesah ustojchivogo razvitija, 2005, vol. 13, pp (in Russ.). 39. Krasutsky P. A. Nat. prod. rep. 2006, vol. 23, no. 6, pp Alakurtti S., Mäkelä T., Koskimies S., Yli-Kauhaluoma J. Europ. J. Pharm. Sciences. 2006, vol. 29, pp Received January 23, 2014 Revised December 10, 2014

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