Abstract
This review summarizes the main methods to introduce a triazole moiety into the structures of a pentacyclic triterpenoid betulin and its derivatives. The prospect of using 1,2,3-triazole-containing triterpenoids as drugs is laid out.
Similar content being viewed by others
REFERENCES
B. Meunier, “Hybrid molecules with a dual mode of action: Dream or reality?,” Acc. Chem. Res. 41, 69–77 (2008).
M. Kvasnica, M. Urban, N. J. Dickinson, and J. Sarek, “Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: Synthesis and medicinal significance,” Nat. Prod. Rep. 32, 1303–1330 (2015).
M. Zhou, R.-H. Zhang, M. Wang, G.-B. Xu, S.-G. Liao, “Prodrugs of triterpenoids and their derivatives,” Eur. J. Med. Chem. 131, 222–236 (2017).
L. Borkova, J. Hodon, and M. Urban, “Synthesis of betulinic acid derivatives with modified a-rings and their development as potential drug candidates,” Asian J. Org. Chem. 7, 1542–1560 (2018).
J. L. C. Sousa, C. S. R. Freire, A. J. D. Silvestre, and A. M. S. Silva, “Recent developments in the functionalization of betulinic acid and its natural analogues: A route to new bioactive compounds,” Molecules 24, 355 (2019).
S. Xiao, Z. Tian, Y. Wang, L. Si, L. Zhang, and D. Zhou, “Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives,” Med. Res. Rev. 38, 951–976 (2018).
J. Hodon, L. Borkova, J. Pokorny, A. Kazakova, and M. Urban, “Design and synthesis of pentacyclic triterpene conjugates and their use in medicinal research,” Eur. J. Med. Chem. 182, 111653–111678 (2019).
V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless, “A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective ‘ligation’ of azides and terminal alkynes,” Angew. Chem. Int. Ed. 41, 2596–2599 (2002).
H. C. Kolb, M. G. Finn, and K. B. Sharpless, “Click Chemistry: Diverse Chemical Function from a Few Good Reactions,” Angew. Chem., Int. Ed. Engl. 40, 2004–2021 (2002).
R. Csuk, A. Barthel, R. Kluge, and D. Strohl, “Synthesis, cytotoxicity and liposome preparation of 28-acetylenic betulin derivatives,” Bioorg. Med. Chem. 18, 7252–7259 (2010).
V. Khwaza, S. Mlala, O. O. Oyedeji, and B. A. Aderibigbe, “Pentacyclic triterpenoids with nitrogen-containing heterocyclic moiety, privileged hybrids in anticancer drug discovery,” Molecules 26, 2401 (2021).
R. Csuk and H. P. Deigner, “The potential of click reactions for the synthesis of bioactive triterpenes,” Bioorg. Med. Chem. Lett. 29, 949–958 (2019).
M. Tomanek, S. Siudak, M. Latocha, and S. Boryczka, “New 30-substituted derivatives of pentacyclic triterpenes: Preparation, biological activity, and molecular docking study,” J. Mol. Struct. 1226, 129394–129404 (2021).
E. Bebenek, M. Kadela-Tomanek, E. Chrobak, M. Jastrzebska, and M. Ksiazek, “Synthesis and structural characterization of a new 1,2,3-triazole derivative of pentacyclic triterpene,” Crystals 12, 422 (2022).
G. Gonzalez, J. Hodon, A. Kazakova, C. D' Acunto, P. Kanovsky, M. Urban, and M. Strnad, “Novel pentacyclic triterpenes exhibiting strong neuroprotective activity in SH-SY5Y cells in salsolinol- and glutamate-induced neurodegeneration models,” Eur. J. Med. Chem. 213, 113168 (2021).
A. Antimonova, N. Petrenko, M. Shakirov, T. Rybalova, T. Frolova, E. Shults, T. Kukina, O. Sinitsyna, and G. Tolstikov, “Synthesis and study of mutagenic properties of lupane triterpenoids containing 1,2,3-triazole fragments in the C-30 position,” Chem. Nat. Compd 49, 657–664 (2013).
J. Pokorny, V. Horka, V. Sidova, and M. Urban, “Synthesis and characterization of new conjugates of betulin diacetate and bis(triphenysilyl)betulin with substituted triazoles,” Monatsh. Chem. 149, 839–845 (2018).
A. P. D. de Souza and S. C. B. Gnoatto, “New triazole triterpene derivative exhibits anti-RSV activity synthesis biological evaluation and molecular modeling,” Beilstein Arch. 202231 (2022).
W. Shi, N. Tang, and W. D. Yan, “Synthesis and cytotoxicity of triterpenoids derived from betulin and betulinic acid via click chemistry,” J. Asian Nat. Prod. Res. 17, 159–169 (2015).
R. Majeed, P. L. Sangwan, P. K. Chinthakindi, I. Khan, N. A. Dangroo, N. Thota, A. Hamid, P. R. Sharma, A. K. Saxena, and S. Koul, “Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents,” Eur. J. Med. Chem. 63, 782–792 (2013).
I. Khan, S. K. Guru, S. K. Rath, P. K. Chinthakindi, B. Singh, S. Koul, S. Bhushan, P. L. Sangwan, “A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells,” Eur. J. Med. Chem. 108, 104–116 (2016).
V. Sidova, P. Zoufaly, J. Pokorny, P. Dzubak, M. Hajduch, I. Popa, and M. Urban, “Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by huisgen cycloaddition from 30-azidoderivatives,” PLOS One 12, 0171621 (2017).
E. Bebenek, M. Jastrzebska, M. Kadela-Tomanek, E. Chrobak, B. Orzechowska, K. Zwolinska, M. Latocha, A. Mertas, Z. Czuba, and S. Boryczka, “Novel triazole hybrids of betulin: Synthesis and biological activity profile,” Molecules 22, 1876 (2017).
E. Bebenek, M. Kadela-Tomanek, E. Chrobak, M. Latocha, and S. Boryczka, “Novel triazoles of 3-acetylbetulin and betulone as anticancer agents,” Med. Chem. Res. 27, 2051–2061 (2018).
T. A. Dang Thi, N. T. Kim Tuyet, C. Pham The, H. Thanh Nguyen, C. Ba Thi, H. Thi Phuong, L. Van Boi, T. Van Nguyen, and M. D’hooghe, “Synthesis and cytotoxic evaluation of novel amide–triazole-linked triterpenoid–AZT conjugates,” Tetrahedron Lett. 56, 218–224 (2015).
P. Suman, A. Patel, L. Solano, G. Jampana, Z. S. Gardner, C. M. Holt, and S. C. Jonnalagadda, “Synthesis and cytotoxicity of Baylis–Hillman template derived betulinic acid-triazole conjugates,” Tetrahedron 73, 4214–4226 (2017).
V. V. Grishko, I. A. Tolmacheva, V. O. Nebogatikov, N. V. Galaiko, A. V. Nazarov, M. V. Dmitriev, and I. B. Ivshina, “Preparation of novel ring-a fused azole derivatives of betulin and evaluation of their cytotoxicity,” Eur. J. Med. Chem. 125, 629–639 (2017).
R. Wang, Y. Li, H. Hu, L. Persoons, D. Daelemans, S. Jonghe, W. Luyten, B. Krasniqi, and W. Dehaen, “Antibacterial and antitumoral properties of 1,2,3-triazolo fused triterpenes and their mechanism of inhibiting the proliferation of HL-60 cells,” Eur. J. Med. Chem. 224, 113727 (2021).
Funding
The work was performed within the framework of a state order, registration no. 122012400109-8.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The authors declare that they have no conflicts of interest.
Additional information
Translated by A. Tulyabaew
Rights and permissions
About this article
Cite this article
Nazarov, M.A., Polovnikova, A.A. & Tolmacheva, I.A. Synthesis of Betulin Conjugates and Its 1,2,3-Triazole Derivatives. Polym. Sci. Ser. D 16, 543–548 (2023). https://doi.org/10.1134/S199542122303022X
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S199542122303022X