Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

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Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo. / Salomatina, Oksana V.; Sen’kova, Aleksandra V.; Moralev, Arseny D. et al.

In: International Journal of Molecular Sciences, Vol. 23, No. 11, 6214, 01.06.2022.

Research output: Contribution to journal › Article › peer-review

BibTeX

@article{b62d63edc8f84beb8b1468cf872d177e,

title = "Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo",

abstract = "It is known that epoxide-bearing compounds display pronounced pharmacological ac-tivities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α-and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexam-ethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.",

keywords = "18βH-glycyrrhetinic acid, ABC transporters, anti-inflammatory activity, anti-metastatic activity, apoptosis, CDDO-Me, epoxide, pharmacophore group, soloxolone methyl, toxicity",

author = "Salomatina, {Oksana V.} and Sen{\textquoteright}kova, {Aleksandra V.} and Moralev, {Arseny D.} and Savin, {Innokenty A.} and Komarova, {Nina I.} and Salakhutdinov, {Nariman F.} and Zenkova, {Marina A.} and Markov, {Andrey V.}",

note = "Funding Information: Funding: This research was supported by the Russian Science Foundation (Grant No. 17-75-20120) (synthesis, in vitro, in silico and in vivo studies) and partly by the Russian State-funded budget project of ICBFM SB RAS No. 121031300044-5 (in the development of basic methods). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = jun,

day = "1",

doi = "10.3390/ijms23116214",

language = "English",

volume = "23",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "11",

}

RIS

TY - JOUR

T1 - Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

AU - Salomatina, Oksana V.

AU - Sen’kova, Aleksandra V.

AU - Moralev, Arseny D.

AU - Savin, Innokenty A.

AU - Komarova, Nina I.

AU - Salakhutdinov, Nariman F.

AU - Zenkova, Marina A.

AU - Markov, Andrey V.

N1 - Funding Information: Funding: This research was supported by the Russian Science Foundation (Grant No. 17-75-20120) (synthesis, in vitro, in silico and in vivo studies) and partly by the Russian State-funded budget project of ICBFM SB RAS No. 121031300044-5 (in the development of basic methods). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - It is known that epoxide-bearing compounds display pronounced pharmacological ac-tivities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α-and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexam-ethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.

AB - It is known that epoxide-bearing compounds display pronounced pharmacological ac-tivities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α-and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexam-ethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.

KW - 18βH-glycyrrhetinic acid

KW - ABC transporters

KW - anti-inflammatory activity

KW - anti-metastatic activity

KW - apoptosis

KW - CDDO-Me

KW - epoxide

KW - pharmacophore group

KW - soloxolone methyl

KW - toxicity

UR - http://www.scopus.com/inward/record.url?scp=85131703860&partnerID=8YFLogxK

U2 - 10.3390/ijms23116214

DO - 10.3390/ijms23116214

M3 - Article

C2 - 35682893

AN - SCOPUS:85131703860

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 11

M1 - 6214

ER -

ID: 36566621