Synthetic Transformations of Higher Terpenoids. 42. Synthesis of New 18-Nor-4-(Carboxyethyl)Isopimara-7,15-Diene Derivatives and Study of Their Cytotoxicity on MCF7, U-87 MG and DU 145 Cancer Cell Lines

M. A. Gromova; Громова М. А.; Y. V. Kharitonov; Харитонов Ю. В.; Т. V. Rybalova; Рыбалова Т. В.; V. А. Larionov; Ларионов В. А.; T. S. Golubeva; Голубева Т. С.; E. E. Shults; Шульц Э. Э.

doi:10.31857/S0132342323050032

Synthetic Transformations of Higher Terpenoids. 42. Synthesis of New 18-Nor-4-(Carboxyethyl)Isopimara-7,15-Diene Derivatives and Study of Their Cytotoxicity on MCF7, U-87 MG and DU 145 Cancer Cell Lines

Authors: Gromova M.A.¹^,2, Kharitonov Y.V.², Rybalova Т.V.², Larionov V.А.³, Golubeva T.S.⁴, Shults E.E.²
Affiliations:
1. Novosibirsk State Pedagogical University (NSPU),
2. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences
3. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences (INEOS RAS)
4. The Federal Research Center Institute of Cytology and Genetics SB RAS (ICG SB RAS)
Issue: Vol 49, No 5 (2023)
Pages: 509-522
Section: Articles
URL: https://journal-vniispk.ru/0132-3423/article/view/139255
DOI: https://doi.org/10.31857/S0132342323050032
EDN: https://elibrary.ru/BLXECA
ID: 139255

Cite item

Full Text

Open Access
Restricted Access

Access granted
Restricted Access

Subscription Access

Abstract
About the authors
References
Supplementary files
Statistics

Abstract

(E)-16-Aryl-substituted derivatives of tricyclic diterpenoids were synthesized by cross-coupling of isopimaric acid derivatives with substituted iodorenes catalyzed by palladium acetate in the presence of silver carbonate. Condensation of (E)-18-nor-4-(carboxyethyl)-16-(2-carboxyethyl)isopimar-7,15-diene dichloride with propargylamine hydrochloride leads to the corresponding dialkine, which readily reacts with diazide in the Cu(I) catalyzed cycloaddition (CuAAC) reaction, with the formation of macroheterocyclic compound containing a pimaran type tricyclic diterpenoid core and 1,2,3-triazole rings in the linker chain. Reaction of in situ prepared (E)-18-nor-16-azido-4-(carboxyethyl)isopimar-7,15-diene acid chloride with propargylamine hydrochloride or an alkynyl-substituted derivative of the protected Gly-Gly dipeptide leads to the corresponding azidoalkynes. The intramolecular CuAAC reaction of azidodipeptidylalkine afforded a macroheterocyclic derivative containing a dipeptide and triazole moiety in the linker chain. The obtained compounds showed higher (compared with the isopimaric acid) cytotoxicity on tumor cells MCF-7 and were less toxic to non-cancer cells than the reference drug doxorubicin. The GI₅₀ value of the most active compound is 6.3 μM, selectivity index >15) (MTT test). The synthesized derivatives of the tricyclic diterpenoid isopimaric acid can be used to develop new antitumor agents.

Keywords

isopimaric acid, diterpenoids, dipeptide, CuAAC-reaction, macrocycles, cytotoxicity

References

Gromova M.A., Kharitonov Yu.V., Borisov S.A., Rybalova T.V., Tolstikova T.G., Shults E.E. // Chem. Nat. Compd. 2022. V. 58. P. 55–64. https://doi.org/10.1007/s10600-022-03596-y
Keeling C.I., Bohlmann J. // Phytochemistry. 2006. V. 67. P. 2415–2423. https://doi.org/10.1016/j.phytochem.2006.08.019
Толстиков Г.A., Толстикова Т.Г., Шульц Э.Э., Толстиков С.E., Хвостов M.В. // Смоляные кислоты хвойных России. Химия и фармакология / Pед. Трофимов Б.A. Новосибирск: Гео, 2011. С. 207–242.
Kugler S., Ossowicz P., Malarczyk-Matusiak K., Wierzbicka E. // Molecules. 2019. V. 24. P. 1651. https://doi.org/10.3390/molecules24091651
Smith E., Williamson E., Zloh M., Gibbons S. // Phytother. Res. 2005. V. 19. P. 538–542. https://doi.org/10.1002/ptr.1711
Coté H., Boucher M.-A., Pichette A., Roger B., Legault J. // J. Ethnopharmacology. 2016. V. 194. P. 684–689. https://doi.org/10.1016/j.jep.2016.10.035
Pferschy-Wenzig E.M., Kunert O., Presser A., Bauer R. // J. Agric. Food Chem. 2008. V. 56. P. 11688–11693. https://doi.org/10.1021/jf8024002
Imaizumi Y., Sakamoto K., Yamada A., Hotta A., Ohya S., Muraki K., Uchiyama M., Ohwada T. // Mol. Pharmacol. 2002. V. 62. P. 836–846. https://doi.org/10.1124/mol.62.4.836
Salari S., Silvera Ejneby M., Brask J., Elinder F. // Acta Physiol. (Oxf.). 2018. V. 222. P. e12895. https://doi.org/10.1111/apha.12895
Ge L., Hoa N.T., Wilson Z., Arismendi-Morillo G., Kong X.-T., Tajhya R.B., Beeton C., Jadus M.R. // Int. Immunopharmacol. 2014. V. 22. P. 427–443. https://doi.org/10.1016/j.intimp.2014.06.040
Sizemore G., McLaughlin S., Newman M., Brundage K., Ammer A., Martin K., Pugacheva E., Coad J., Mattes M.D., Yu H.-G. // BMC Cancer. 2020. V. 20. P. 595. https://doi.org/10.1186/s12885-020-07071-1
Lu Y., Zhao Z., Chen Y., Wang J. // Lett. Org. Chem. 2021. V. 18. P. 950–956. https://doi.org/10.2174/1570178618666210813121953
Lu Y.-J., Zhao Z.-D., Chen Y.-X., Wang J., Xu S.-C., Gu Y. // J. Asian Nat. Prod. Res. 2020. V. 23. P. 545–555. https://doi.org/10.1080/10286020.2020.1810668
Liu J., Lu Y., Wang J., Bi L., Zhao Z. // Chin. J. Org. Chem. 2017. V. 37. P. 731–738. https://doi.org/10.6023/cjoc201610017
Gromova M.A., Kharitonov Yu.V., Pokrovskii M.A., Bagryanskaya I.Yu., Pokrovskii A.G., Shul’ts E.E. // Chem. Nat. Compd. 2019. V. 55. P. 52–59. https://doi.org/10.1007/s10600-019-02613-x
Gromova M.A., Kharitonov Yu.V., Golubeva T.S., Shults E.E. // Macroheterocycles. 2021. V. 14. P. 231–239. https://doi.org/10.6060/mhc210945s
Gromova M.A., Kharitonov Yu.V., Rybalova T.V., Shults E.E. // Monatsh. Chem. 2020. V. 151. P. 1817–1827. https://doi.org/10.1007/s00706-020-02713-3
Gromova M.A., Kharitonov Y.V., Rybalova T.V., Shults E.E. // Macroheterocycles. 2021. V. 14. P. 105–111. https://doi.org/10.6060/mhc200817s
Zhao S., Wang Z-P., Wen X., Li S., Wei G., Guo J., He Y. // Org. Lett. 2020. V. 22. P. 6632–6636. https://doi.org/10.1021/acs.orglett.0c02403
Thirumurugan P., Matosiuk D., Jozwiak K. // Chem. Rev. 2013. V. 113. P. 4905–4979. https://doi.org/10.1021/cr200409f
Klein E., DeBonis S., Thiede B., Skoufias D.A., Kozielski F., Lebeau L. // Bioorg. Med. Chem. 2007. V. 15. P. 6474–6488. https://doi.org/1016/j.bmc.2007.06.016
Spek A.L. // J. Appl. Cryst. 2003. V. 36. P. 7–13. https://doi.org/10.1107/S0021889802022112
Wilson J.K., Sargent J.M., Elgie A.W., Hill J.G., Taylor C.G. // Br. J. Cancer. 1990. V. 62. P. 189–194. https://doi.org/10.1038/bjc.1990.258
Kharitonov Yu.V., Shakirov M.M., Shul’ts E.E. // Chem. Nat. Compd. 2014. V. 49. P. 1067–1075. https://doi.org/10.1007/s10600-014-0823-1
Zhang Z., Xiao F., Huang B., Hu J., Fu B., Zhang Z. // Org. Lett. 2016. V. 18. P. 908–911. https://doi.org/10.1021/acs.orglett.6b00607
Wang H., He C., Pan Y., Yao C., Wu Q., Deng H. // J. Incl. Phenom. Macrocycl. Chem. 2012. V. 73. P. 177–183. https://doi.org/10.1007/s10847-011-0040-5
Larionov V.A., Adonts H.V., Gugkaeva Z.T., Smol’yakov A.F., Saghyan A.S., Miftakhov M.S., Kuznetsova S.A., Maleev V.I., Belokon Yu.N. // ChemistrySelect. 2018. V. 3. P. 3107–3110. https://doi.org/10.1002/slct.201800228
Krause L., Herbst-Irmer R., Sheldrick G.M., Stalke D. // J. Appl. Cryst. 2015. V. 48. P. 3–10. https://doi.org/10.1107/S1600576714022985
Sheldrick G.M. // Acta Crystallogr. 2015. A71. P. 3–8. https://doi.org/10.1107/S2053273314026370