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Pentacyclic triterpene acid conjugated with mitochondria-targeting cation F16: Synthesis and evaluation of cytotoxic activities

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Abstract

The first representatives of F16-conjugated pentacyclic triterpenoids, betulin and betulinic, ursolic, oleanolic, and glycyrrhetic acid derivatives, were synthesized. The triterpene core was linked, at the С-3, С-28, or С-30 position, to one or two mitochondria-targeting delocalized lipophilic cations F16 via butane or triethylene glycol spacer. The human cancer cell lines U937 (leukemic monocyte lymphoma), K562 (chronic myeloid leukemia), and Jurkat (T-lymphoblastic leukemia), and a human nonmalignant fibroblast cell line were used to evaluate the cytotoxic activities of the products. Most of the obtained conjugates showed considerable enhancement of the antitumor action in comparison with the parent betulinic acid (≈100−200-fold) and a markedly higher cytotoxic effect against tumor cell lines over healthy fibroblast cells. In the series of test compounds, F16 conjugates with betulin and betulinic acid 6, 8, and 11 were most selective, showing acceptable values of selectivity index (≥10).

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Acknowledgements

This work was performed under financial support from the Russian Science Foundation (Grant 19-73-00155). The structural studies of the synthesized compounds were performed with the use of Collective Usage Centre “Agidel” at the Institute of Petrochemistry and Catalysis of RAS.

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Authors and Affiliations

  1. Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa, 450075, Russian Federation

    Anna Yu. Spivak, Darya A. Nedopekina, Rinat R. Gubaidullin, Eldar V. Davletshin, Adis A. Tukhbatullin, Vladimir A. D’yakonov, Milyausha M. Yunusbaeva, Lilya U. Dzhemileva & Usein M. Dzhemilev

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  1. Anna Yu. Spivak
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  2. Darya A. Nedopekina
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  3. Rinat R. Gubaidullin
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  5. Adis A. Tukhbatullin
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  6. Vladimir A. D’yakonov
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Correspondence to Anna Yu. Spivak.

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Spivak, A.Y., Nedopekina, D.A., Gubaidullin, R.R. et al. Pentacyclic triterpene acid conjugated with mitochondria-targeting cation F16: Synthesis and evaluation of cytotoxic activities. Med Chem Res 30, 940–951 (2021). https://doi.org/10.1007/s00044-021-02702-z

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