Synthesis and characterization of carborane-functionalized hyperbranched polyester for boron neutron capture therapy

Öz

The purpose of this study is to synthesize new boron containing carrier compound for Boron Neutron Capture Therapy (BNCT) which is two-component radiation therapy method that especially is promising for the treatment of brain tumors and is being actively researched in many countries. For this research hyperbranched polyester (HBP), bifunctional p-carborane and carborane-functionalized HBP were synthesized. Dipentaerythritol was chosen as a core molecule of the HBP and esterified with dimethylol propionic acid. Observed characteristic ester bands and OH stretching band in the FTIR spectrum and the methyl & methylene peaks in the 1H NMR spectrum of HBP indicated that hyperbranched polyester synthesis was done successfully. A bifunctionalized p-carborane containing an acid group and a benzyl ether protected alcohol was prepared in three-step reactions. As a result of these reactions, a bifunctionalized p-carborane compound was produced with 60% yield. Then, the HBP was esterified with the bifunctional p-carborane. The characterization of the synthesized compounds was determined by FTIR and NMR spectra. The synthesis of carborane-functionalized HBP was confirmed by disappearance of HBP's OH groups and B-H stretching band observed in the FTIR spectrum of carborane-functionalized HBP and in addition, appearance of proton signals of HBP core, carborane linker and peripheral-protecting groups in the 1H-NMR spectrum. Finally, synthesized water-soluble carborane-containing HB carrying many boron atoms should be served as potential BNCT agents.

Anahtar Kelimeler

• Bnct
• boron
• carborane
• esterification
• hyperbranced polyester

Kaynakça

1. [1]Endo, Y (2018). Carboranes as hydrophobic pharma-cophores: applications for design of nuclear receptor ligands. In Hey-Hawkins E. & Texidior C. V. (Eds.), Boron-based compounds: Potential and emerging ap-plications in medicine (pp. 3-19). John Wiley & Sons Ltd.
2. [2] Parrott, M. C., Marchington, E. B., Valliant, J. F., & Adronov, A. (2005). Synthesis and properties of car-borane-functionalized aliphatic polyester dendrimers. Journal of the American Chemical Society, i27(34), 12081-12089.
3. [3] Barth, R. F., Coderre, J. A., Vicente, M. G. H., & Blue,T. E. (2005). Boron neutron capture therapy of cancer:current status and future prospects. Clinical Cancer Research, 11(11), 3987-4002.
4. [4] Hu, K., Yang, Z., Zhang, L., Xie, L., Wang, L., Xu, H., ...& Zhang, M. R. (2020). Boron agents for neutron capture therapy. Coordination Chemistry Reviews, 4C5, 213139.
5. [5] Hawthorne, M. F. (1993). The role of chemistry in the development of boron neutron capture therapy of can-cer. Angewandte Chemie international Edition in Eng¬lish, 32(7), 950-984.
6. [6] Bat, E. (2005). Synthesis and characterization of hy-perbranched and air drying fatty acid based resins [MSC Thesis, Middle East Technical University, Gradu-ate School of Natural and Applied Sciences]. Council of Higher Education Thesis Center (Thesis Number 166837).
7. [7] Gao, C., & Yan, D. (2004). Hyperbranched polymers: from synthesis to applications. Progress in polymer science, 29(3), 183-275.
8. [8] Kim, Y H. (1998). Hyperbranched polymers 10 years after. Journal of Polymer Science Part A: Polymer Chemistry, 36(11), 1685-1698.

9. [9] Uhrich, K. (1997). Hyperbranched polymers for drug delivery. Trends in Polymer Science, l2(5), 388-393.
10. [10] Cheng, K. C., & Wang, L. Y. (2002). Kinetic model of hyperbranched polymers formed in copolymerization of AB2 monomers and multifunctional core molecules with various reactivities. Macromolecules, 35(14), 5657-5664.
11. [11] Liu, H., Näsman, J. H., & Skrifvars, M. (2000). Radi¬cal alternating copolymerization: A strategy for hyper-branched materials. Journal of Polymer Science Part A: Polymer Chemistry, 38(17), 3074-3085.
12. [12] Kuchanov, S., Slot, H., & Stroeks, A. (2004). Devel-opment of a quantitative theory of polycondensation. Progress in polymer science, 29(6), 563-633.
13. [13] Cheng, K. C., Chuang, T. H., Tsai, T. H., Guo, W., & Su, W. F. (2008). Model of hyperbranched polymers formed by monomers A2 and Bg with end-capping molecules. European polymer journal, 44(9), 2998¬3004.
14. [14] Fradet, A., & Tessier, M. (2007). First Shell Substitu¬tion Effects in Hyperbranched Polymers: Kinetic- Re¬cursive Probability Analysis. Macromolecules, 40(20), 7378-7392.
15. [15] Jikei, M., Chon, S. H., Kakimoto, M. A., Kawauchi, S., & Imase, T (1999). Synthesis of hyperbranched aro¬matic polyamide from aromatic diamines and trimesic acid. Macromolecules, 32(6), 2061-2064.
16. [16] Liu, Q., Zhao, P., & Chen, Y. (2007). Divergent syn-thesis of dendrimer-like macromolecules through a combination of atom transfer radical polymerization and click reaction. Journal of Polymer Science Part A: Polymer Chemistry, 45(15), 3330-3341.
17. [17] Hirao, A., Matsuo, A., & Watanabe, T (2005). Precise synthesis of dendrimer-like star-branched poly (methyl methacrylate) s up to seventh generation by an itera¬tive divergent approach involving coupling and trans-formation reactions. Macromolecules, 38(21), 8701¬8711.
18. [18] Bai, Y, Song, N., Gao, J. P., Sun, X., Wang, X., Yu, G., & Wang, Z. Y (2005). A new approach to highly electrooptically active materials using cross-linkable, hyperbranched chromophore-containing oligomers as a macromolecular dopant. Journal of the American Chemical Society, 127(7), 2060-2061.
19. [19] Powell, K. T., Cheng, C., & Wooley, K. L. (2007). Com-plex amphiphilic hyperbranched fluoropolymers by atom transfer radical self-condensing vinyl (co) polym-erization. Macromolecules, 40(13), 4509-4515.
20. [20] Cheng, K. C., Chuang, T H., Chang, J. S., Guo, W., & Su, W. F. (2005). Effect of feed rate on structure of hyperbranched polymers formed by self-condensing vinyl polymerization in semibatch reactor. Macromol-ecules, 38(20), 8252-8257.
21. [21] Cheng, K. C. (2003). Kinetic model of hyperbranched polymers formed by self-condensing vinyl polymeriza-tion of AB* monomers in the presence of multifunction¬al core molecules with different reactivities. Polymer, 44(3), 877-882.
22. [22] Zagar, E., & Zigon, M. (2011). Aliphatic hyperbranched polyesters based on 2, 2-bis (methylol) propionic acid- Determination of structure, solution and bulk proper¬ties. Progress in Polymer Science, 36(1), 53-88.
23. [23] Mesias, R., & Murillo, E. A. (2015). Hyperbranched polyester polyol modified with polylactic acid. Journal of Applied Polymer Science, 132(10), 44-52.
24. [24] Murillo, E. A., Vallejo, P. P., Sierra, L., & López, B. L. (2009). Characterization of hyperbranched polyol poly-esters based on 2, 2-bis (methylol propionic acid) and pentaerythritol. Journal of Applied Polymer Science, 112(1), 200-207.
25. [25] Mishra, A. K., Jena, K. K., & Raju, K. V. S. N. (2009). Synthesis and characterization of hyperbranched poly- ester-urethane-urea/K10-clay hybrid coatings. Pro¬gress in Organic Coatings, 64(1), 47-56.
26. [26] Kutyreva, M. P., Usmanova, G. S., Ulakhovich, N. A., & Kutyrev, G. A. (2010). Polynuclear Cu (II) complexes with hyperbranched polyester carboxylates. Russian Journal of General chemistry, 80(4), 787-789.
27. [27] Murillo, E. A., Vallejo, P P, & López, B. L. (2011). Ef¬fect of tall oil fatty acids content on the properties of novel hyperbranched alkyd resins. Journal of Applied Polymer Science, 120(6), 3151-3158.
28. [28] Mesias, R., & Murillo, E. (2018). Hyperbranched pol-yester polyol modified with polylactic acid as a com- patibilizer for plasticized tapioca starch/polylactic acid blends. Polímeros, 28(1), 44-52.
29. [29] Jovicic, M., Radicevic, R., Pavlicevic, J., Bera, O., & Govedarica, D. (2020). Synthesis and characterization of ricinoleic acid based hyperbranched alkyds for coat-ing application. Progress in Organic Coatings, 148, 105832.
30. [30] Bat, E., Gündüz, G., Kısakürek, D., & Akhmedov, İ. M. (2006). Synthesis and characterization of hyper-branched and air drying fatty acid based resins. Pro-gress in Organic Coatings, 55(4), 330-336.
31. [31] Malmström, E., Johansson, M., & Hult, A. (1995). Hy-perbranched aliphatic polyesters. Macromolecules, 28(5), 1698-1703.
32. [32] Barth, R. F., Adams, D. M., Soloway, A. H., Alam, F, & Darby, M. V. (1994). Boronated starburst dendrimer- monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture ther¬apy. Bioconjugate chemistry, 5(1), 58-66.
33. [33] Sauter, G., Maeda, T., Waldman, F. M., Davis, R. L., & Feuerstein, B. G. (1996). Patterns of epidermal growth factor receptor amplification in malignant gliomas. The American journal of pathology, 148(4), 1047-1053. [34] Gillies, E. R., & Frechet, J. M. (2005). Dendrimers and dendritic polymers in drug delivery. Drug discovery to-day, 10(1), 35-43.
34. [35] Ihre, H. R., Padilla De Jesús, O. L., Szoka, F C., & Fré- chet, J. M. (2002). Polyester dendritic systems for drug delivery applications: design, synthesis, and charac-terization. Bioconjugate chemistry, 13(3), 443-452.
35. [36] Yao, H., Grimes, R. N., Corsini, M., & Zanello, P (2003). Polynuclear Metallacarborane- Hydrocarbon Assemblies: Metallacarborane Dendrimers. Organo- metallics, 22(22), 4381-4383.
36. [37] Núñez, R., González, A., Viñas, C., Teixidor, F., Sil- lanpââ, R., & Kivekâs, R. (2005). Approaches to the preparation of carborane-containing carbosilane com-pounds. Organic letters, 7(2), 231-233.
37. [38] Qualmann, B., Kessels, M. M., Musiol, H. J., Sierralta, W. D., Jungblut, P W., & Moroder, L. (1996). Synthe¬sis of boron-rich lysine dendrimers as protein labels in electron microscopy. Angewandte Chemie Interna¬tional Edition in English, 35(8), 909-911.
38. [39] Armspach, D., Cattalini, M., Constable, E. C., House-craft, C. E., & Phillips, D. (1996). Boron-rich metalloden- drimers—mix-and-match assembly of multifunctional metallosupramolecules. Chemical Communications,(15) , 1823-1824. [40] Newkome, G. R., Keith, J. M., Baker, G. R., Escamilla, G. H., & Moorefield, C. N. (1994). Chemistry within a Unimolecular Micelle Precursor: Boron Superclusters by Site- and Depth-Specific Transformations of Den- drimers. Angewandte Chemie International Edition in English, 33(6), 666-668.
39. [41] Ihre, H., Padilla De Jesús, O. L., & Frechet, J. M. (2001). Fast and convenient divergent synthesis of all phatic ester dendrimers by anhydride coupling. Jour¬nal of the American Chemical Society, 123(25), 5908¬5917.
40. [42] Ihre, H., Hult, A., & Soderlind, E. (1996). Synthesis, characterization, and 1H NMR self-diffusion studies of dendritic aliphatic polyesters based on 2, 2-bis (hy- droxymethyl) propionic acid and 1, 1, 1-tris (hydroxy- phenyl) ethane. Journal of the American Chemical So-ciety, 118(27), 6388-6395.
41. [43] Ihre, H., Hult, A., Fréchet, J. M., & Gitsov, I. (1998). Double-stage convergent approach for the synthesis of functionalized dendritic aliphatic polyesters based on 2, 2-bis (hydroxymethyl) propionic acid. Macromol-ecules, 31(13), 4061-4068.
42. [44] Padilla De Jesús, O. L., Ihre, H. R., Gagne, L., Fréchet, J. M., & Szoka, F. C. (2002). Polyester dendritic sys¬tems for drug delivery applications: in vitro and in vivo evaluation. Bioconjugate chemistry, 13(3), 453-461.
43. [45] Galie, K. M., Mollard, A., & Zharov, I. (2006). Polyes¬ter-based carborane-containing dendrons. Inorganic chemistry, 45(19), 7815-7820.
44. [46] Mollard, A., & Zharov, I. (2006). Tricarboranyl pen- taerythritol-based building block. Inorganic chemistry, 45(25), 10172-10179.
45. [47] Dubey, R., Kushal, S., Mollard, A., Vojtovich, L., Oh, P, Levin, M. D., ... & Olenyuk, B. Z. (2015). Tumor target-ing, trifunctional dendritic wedge. Bioconjugate chem-istry, 26(1), 78-89.
46. [48] Benhabbour, S. R., Parrott, M. C., Gratton, S. E., & Adronov, A. (2007). Synthesis and properties of car- borane-containing dendronized polymers. Macromol-ecules, 40(16), 5678-5688.