Bioengineering Functional Copolymers. XX. Synthesis of Novel Anticancer Active Poly maleic anhydride-alt-2-vinyl-1,3-dioxolane and its Organoboron Amide-Ester Branched Derivatives ​

Yıl 2012, Cilt: 40 Sayı: 2, 183 - 194, 01.04.2012

Gülten Kahraman Mustafa Türk Zakir M.o. Rzayev Ernur A. Söylemez Serpil Oğuztüzün

Öz

Novel bioengineering alternating copolymer and its organoboron amide and a-hydroxy-w- methoxypoly ethylene oxide PEO branched derivatives were synthesized by 1 complex-radical alternating copolymerization of two non-homopolymerizable in chosen reaction conditions monomers such as maleic anhydride MA and 2-vinyl-1,3-dioxolane VDO , 2 amidolysis of synthesized poly MA-alt-VDO with 2-aminoethyldiphenylboronate and 3 esterification-grafting of organoboron copolymer with PEO. The complex-formation Kc and the monomer reactivity ratios r1 and r2 copolymerization constants , structure and composition of the synthesized copolymers were characterized by chemical alkali titration , FTIR-ATR and NMR spectroscopy, TGA-DSC thermal analysis methods. Cytotoxicity found as having an order as organoboron branched PEO copolymer < poly MA-alt-VDO < organoboron copolymer of these novel copolymers containing a combination of ionizable, hydrophilic/hydrophobic, organoboron, carboxyl-amide-ester-ether groups, toward HeLa cells was investigated.

Anahtar Kelimeler

Synthesis, Alternating copolymer, Amidolysis, Esterification, Organoboron copolymer, Citotoxicity, HeLa cells

Biyomühendislik Fonksiyonel Kopolimerleri. XX. Yeni Antikanser Aktif Poli maleik anhidrid-alt-2- vinil-1,3-dioxolan ve Organoboron Amid-Ester Dallanmış Türevleri

Öz

Y eni biyomühendislik alternatif kopolimerinin ve organobor amid ve a-hidroksi-w-metoksi-poli etilen oksit PEO ile dallanmış türevlerinin sentezi, 1 Seçilen reaksiyon şartlarında homopolimerleşmeyen maleik anhidriti MA ve 2-vinil-1,3-dioksolan VDO monomerlerinin kompleks-radikal alternatif kopolimerizasyonu, 2 sentezlenenpoli MA-alt-VDO makromoleküllerinin 2-amino-etildifenilboronat ile amidolizi ve 3 PEO ile esterleşmesi yöntemleri kulllanarak gerçekleştirilmiştir. Monomerlerin kompleks oluşumu K ve kopolimerleşme sabitleri r1 ve r2 , çok fonksiyonel gruplar içeren kopolimerlerin yapısı, içeriği ve ısısal özellikleri kimyasal analiz alkali titrasyon , FTIR-ATR and NMR spektroskopisi ve TGA-DSC ile karakterize edilmiştir. İyonize olabilen, hidrofilik/hidrofobik, organobor, anhidrit-karboksil-amid-ester-eter gibi gruplar içeren bu kopolimerlerin HeLa hücrelerine sitotoksik etkisi araştırılmış ve organobor-PEO kopolimer < poli MAalt-VDO < organobor kopolimer sırasında olduğu belirlenmiştir

Anahtar Kelimeler

Sentez, Alternatif kopolimer, Amidoliz, Esterleşme, Organobor kopolimer, Sitotoksisite, HeLa hücreleri

Kaynakça

• 1. K. Ulbrich, T. Etrych, P. Chytil, M. Jelnkova, B. Rhova, J. Cont. Release, 87 (2003) 33.
• 2. GB. Butler, Cyclopolymerization and cyclocopolymerization, (1992). New York, Marcel Dekker.
• 3. S. Iwatsuki, Y. Yamashita, The charge transfer complex formation between p-dioxene and maleic anhydride and their participation in polymerization, Makromol. Chem., 89 (1965) 205.
• 4. T. Kokubo, S. Iwatsuki, Y. Tamashita, Studies on the charge-transfer complex and polymerization. XVII. The reactivity of the charge-transfer complex in alternating radical copolymerization of vinyl ethers and maleic anhydride, Macromol., 1 (1968) 482.
• 5. T. Kokubo, S. Iwatsuki, Y. Tamashita, Studies on the charge-transfer complex and polymerizations, Part XIX. Spontaneous copolymerization of 1.2-dimethoxyethylen and p-dioxene with maleic anhydride, Makromol. Chem., 123 (1969) 256.
• 6. K. Fujimori, Copolymerization of 2,3-dihydropyran and ethyl vinyl ether with maleic anhydride, J. Macromol. Sci.-Chem A, 9 (1975) 495.
• 7. Z.M. Rzayev, L.V. Bryksina, S.I. Sadikh-zade, Charge Transfer Complexes of maleic anhydride in radical homo-and copolymerization, J. Polym. Sci. Part 1: Symp., 42 (1973) 519.
• 8. M.J. Han, K.H. Kim, T.J. Cho, K.B. Choi, Synthesis and characterization of poly[(3,4-dihydro-2hpyran)-alt-(maleic anhydride)] and its derivatives: Biologically active polymers, J. Polym. Sci. Part A: Polym. Chem., 28 (1990) 2719.
• 9. M.J. Han, K.S. Kim, T.J. Cho, K.H. Kim, J.Y. Chang, Polyribonucleotide Analogs: Synthesis and Physicochemical Properties, Macromolecules, 27 (1994) 2896.
• 10. I.G. Donaruma, Anionic polymeric drugs, (1980), New York, Wiley.
• 11. H.K. Can, A.L. Doğan, Z.M.O. Rzayev, A.H. Üner, A. Güner, Synthesis and antitumor activity of poly(3,4- dihydro-2H-pyran-co-maleic anhydride-co-vinylacetate), J. Appl. Polym. Sci., 96 (2005) 2352.
• 12. Z.MO. Rzayev, M. Türk, A. Uzgören, Bioengineering functional copolymers. XV. Synthesis and characterization of poly(N-isopropyl acrylamideco-3,4-dihydro-2H-pyran-alt-maleic anhydride) s and their PEO branched derivatives, J. Polym. Sci. Part A: Polym. Chem., 48 (2010) 4285.
• 13. M. Türk, Z.M.O. Rzayev, S.A. Khalilova, Bioengineering functional copolymers. XIV. Synthesis and interaction of poly(isopropyl acrylamide-co-2,3-dihydro-2Hpyran-alt-maleic anhydride)s with SCLC cancer cells, Bioorg. Med. Chem., 18 (2010) 7975.
• 14. Y.K. Han, S.K. Choi, Synthesis and polymerization of 8,9-benzo-2-methylene-1,4,6-trioxaspiro[4,4] nonane (BMTN), J. Polym. Sci. Polym. Chem. Ed., 21 (1983) 353.
• 15. T. Otsu, H. Inoue, Alternative copolymerization of vinyl sulfides with maleic anhydride, III. Alternative copolymerization, Makromol. Chem., 128 (1969) 31.
• 16. K. Fujimori, A. Wickramasinghe, The reactivity of the charge-transfer complex od butyl vinyl ether and maleic anhydride in the radical terpolymerization of butyl vinyl ether, Austral. J. Chem., 33 (1980) 189
• 17. A.I. Smirnov, G.I. Deryabina, A.B. Kalabina, T.L. Petrova, IL. Stoyachenko, VB. Golubev, VP. Zubov, Inves-tigation of alternating copolymerization mechanizm of vinyl ethers with derivatives of maleic acid, Vysokomol. Soyed. A., 20 (1978) 1794.
• 18. Z.M.O. Rzayev, Complex-radical alternating copolymerization, Prog. Polym. Sci., 25 (2000) 163.
• 19. L.M. Croll, H.D.H. Stover, Mechanism of selfassembly and rupture of crosslinked microspheres and microgels at the oil-water interface, Langmuir, 19 (2003) 10077.
• 20. M.Q. Zhu, L.H. Wei, M. Li, L. Jiang, F.S. Du, Z.C. Li, A unique synthesis of a well-defined block copolymer having alternating segments constituted by maleic anhydride and styrene and the self-assembly aggregating behavior thereof, Chem. Commun. 4 (2001) 365.
• 21. M.C. Davies, J.V. Dawkins, D.J. Hourston, Radical copolymerization of maleic anhydride and substituted styrenes by reversible addition-fragmentation chain transfer (RAFT) polymerization, Polymer, 46 (2005) 1739.
• 22. G. Kahraman, O. Beskardes, Z.M.O. Rzaev, E. Piskin, Bioengineering polyfunctional copolymers. VII. Synthesis and characterization of copolymers of p-vinylphenyl boronic.acid with maleic and citraconic anhydrides and their self-assembled macrobranched supramolecular architectures, Polymer 45 (2004) 5813
• 23. E. Chernikova, P. Terpugova, C. Bui, B. Charleux, Effect of comonomer composition on the controlled free-radical copolymerization of styrene and maleic anhydride by reversible addition–fragmentation chain transfer (RAFT), Polymer, 44 (2003) 4101.
• 24. H. Kesim, Z.M.O. Rzaev, S. Dinçer, E. Piskin, Functional bioengineering copolymers. I. Synthesis and characterization of amphiphilic poly(Nisopropylacrylamide-co-maleic anhydride) and its macrobranched derivatives, Polymer, 44 (2003) 2897.
• 25. M.C. Davies, J.V. Dawkins, D.J. Hourston, E. Meehan, Molar mass determination of poly(octadecenealt-maleic anhydride) copolymers by size exclusion chromatography and dilute solution viscometry, Polymer, 43 (2002) 4311.
• 26. J. Zhou, L. Wang, C. Wang, T. Chen, H. Yu, Q. Yang, Synthesis and self-assembly of amphiphilic maleic anhydride–stearyl methacrylate copolymer, Polymer, 46 (2005) 11157.
• 27. F. Delie, M.J. Blanco-Prieto, Polymeric particulates to improve oral bioavailability of peptide drugs. Molecules, 10 (2005) 65.
• 28. R.W. Blevins (Eastman Chem. Co., USA), Copolymers of dioxolanes and maleic anhydride, Eur. Pat. 0522046 B1 (1991).
• 29. A.S. Hoffman, Polymeric particulates to improve oral bioavailability of peptide drugs, Artif. Organs. 19 (1995) 458.
• 30. I.Y. Galaev, B. Mattiasson, ‘Smart’ polymers and what they could do in biotechnology and medicine, Trends Biotechnol., 17 (1999) 335.
• 31. J.L. Moreau, D. Kesselman, J. Fisher, Synthesis and properties of cyclic acetal biomaterials, J. Biomed. Mater. Res. A, 81 (2007) 594.
• 32. M.W. Betz, P.C. Modi, J.F. Caccamese, D.P. Coletti, J.J. Sauk, J.P. Fisher, Cyclic acetal hydrogel system for bone marrow stromal cell encapsulation and osteodifferentiation, J. Biomed. Mater. Res. A., 86 (2008) 662.
• 33. S. Kaihara, S. Matsumura, J.P. Fisher, Synthesis and characterization of cyclic acetal based degradable hydrogels, EU J. Pharm. Biopharm., 68 (2008) 67.
• 34. N.A. Petasis, Expanding roles for organoboron compounds-versatile and valuable molecules for sythetic, biological and medicinal chemistry, Aust. J. Chem., 60 (2007) 795.
• 35. W. Yang, X. Gao, B. Wang, Boronic acid compounds as potential pharmaceutical agents, Med. Res. Rev., 23 (2003) 346.
• 36. S. Shi, H. Gao, G. Wu, J. Nie, Cyclic acetal as coinitiator for bimolecular photoinitiating systems, Polymer, 48 (2007) 2860.
• 37. M. Patel, M.W. Betz, E. Geibel, K.J. Pateş, J.F. Caccamese, D.P. Coletti, J.J. Sauk, J.P. Fisher, Cyclic acetal hydroxyapatite nanocomposites for orbital bone regeneration, Tissue Eng Part A., 16 (2010) 55.
• 38. J.F. Valliant, K.J. Guenther, A.S. King, P. Morel, P. Schaffer, OO. Sogbein, K.A. Stephenson, The medical chemistry of carborones, Coord. Chem. Rev., 232 (2002) 173.
• 39. W. Chen, S.C. Mehta, D.R. Lu, Selective boron drug delivery to brain tumor for boron neutron capture therapy, Adv. Drug. Deliv. Rev., 26 (1997) 231.
• 40. Z.M.O. Rzayev, M. Türk, G. Kahraman, E. Pişkin, Bioengineering functional copolymers, XIX. Synthesis of anhydride-organoboron functionalized copolymers and their interaction with cancer cells, Hacettepe J. Biol. & Chem., 39 (2011) 111.
• 41. M. Türk, G. Kahraman, S.A. Khalilova, Z.M.O. Rzayev, S. Oğuztüzün, Bioengineering functional copolymers. XVII. Interaction of organoboron amide-ester branched derivatives of poly(acrylic acid) with cancer cells, J. Cancer Therapy, 2 (2011) 266.
• 42. M.W. Hanna, A.L. Ashbauch, Nuclear magnetic resonance study of molecular complexes of 7, 7, 8, 8– tetracyanoquinodimethane and aromatic donors, J. Phys. Chem. 68 (1964) 81.
• 43. T. Kelen, F. Tüdös, Analysis of the linear methods for determining copolymerization reactivity ratios. I. A new improved linear graphic method, J. Macromol. Sci. Part A: Chem. 9 (1975) 1.
• 44. P. Comes, W.W. Franke, Composition, structure and function of HeLa cell nuclear envelope, I. Structural data, Z. Zellforsch., 107 (1970) 240.