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Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. / Il'ina, Irina V.; Dyrkheeva, Nadezhda S.; Zakharenko, Alexandra L. et al.

In: Molecules (Basel, Switzerland), Vol. 25, No. 15, 3496, 08.2020.

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

Harvard

Il'ina, IV, Dyrkheeva, NS, Zakharenko, AL, Sidorenko, AY, Li-Zhulanov, NS, Korchagina, DV, Chand, R, Ayine-Tora, DM, Chepanova, AA, Zakharova, OD, Ilina, ES, Reynisson, J, Malakhova, AA, Medvedev, SP, Zakian, SM, Volcho, KP, Salakhutdinov, NF & Lavrik, OI 2020, 'Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1', Molecules (Basel, Switzerland), vol. 25, no. 15, 3496. https://doi.org/10.3390/molecules25153496

APA

Il'ina, I. V., Dyrkheeva, N. S., Zakharenko, A. L., Sidorenko, A. Y., Li-Zhulanov, N. S., Korchagina, D. V., Chand, R., Ayine-Tora, D. M., Chepanova, A. A., Zakharova, O. D., Ilina, E. S., Reynisson, J., Malakhova, A. A., Medvedev, S. P., Zakian, S. M., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2020). Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules (Basel, Switzerland), 25(15), [3496]. https://doi.org/10.3390/molecules25153496

Vancouver

Il'ina IV, Dyrkheeva NS, Zakharenko AL, Sidorenko AY, Li-Zhulanov NS, Korchagina DV et al. Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules (Basel, Switzerland). 2020 Aug;25(15):3496. doi: 10.3390/molecules25153496

Author

Il'ina, Irina V. ; Dyrkheeva, Nadezhda S. ; Zakharenko, Alexandra L. et al. / Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. In: Molecules (Basel, Switzerland). 2020 ; Vol. 25, No. 15.

BibTeX

@article{476c1645a27f46eeb4b39b414b0f7a55,
title = "Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1",
abstract = "Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 -/- cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.",
keywords = "carene, inhibitor, monoterpene, synergy, TDP1 gene knockout cells, topotecan, tyrosyl-DNA phosphodiesterase 1, ISOMERIZATION, TYROSYL-DNA PHOSPHODIESTERASE, GENOME, TDP1gene knockout cells, IMPACT, VAPOR-PHASE",
author = "Il'ina, {Irina V.} and Dyrkheeva, {Nadezhda S.} and Zakharenko, {Alexandra L.} and Sidorenko, {Alexander Yu} and Li-Zhulanov, {Nikolay S.} and Korchagina, {Dina V.} and Raina Chand and Ayine-Tora, {Daniel M.} and Chepanova, {Arina A.} and Zakharova, {Olga D.} and Ilina, {Ekaterina S.} and J{\'o}hannes Reynisson and Malakhova, {Anastasia A.} and Medvedev, {Sergey P.} and Zakian, {Suren M.} and Volcho, {Konstantin P.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",
year = "2020",
month = aug,
doi = "10.3390/molecules25153496",
language = "English",
volume = "25",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "15",

}

RIS

TY - JOUR

T1 - Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

AU - Il'ina, Irina V.

AU - Dyrkheeva, Nadezhda S.

AU - Zakharenko, Alexandra L.

AU - Sidorenko, Alexander Yu

AU - Li-Zhulanov, Nikolay S.

AU - Korchagina, Dina V.

AU - Chand, Raina

AU - Ayine-Tora, Daniel M.

AU - Chepanova, Arina A.

AU - Zakharova, Olga D.

AU - Ilina, Ekaterina S.

AU - Reynisson, Jóhannes

AU - Malakhova, Anastasia A.

AU - Medvedev, Sergey P.

AU - Zakian, Suren M.

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

PY - 2020/8

Y1 - 2020/8

N2 - Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 -/- cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

AB - Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 -/- cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

KW - carene

KW - inhibitor

KW - monoterpene

KW - synergy

KW - TDP1 gene knockout cells

KW - topotecan

KW - tyrosyl-DNA phosphodiesterase 1

KW - ISOMERIZATION

KW - TYROSYL-DNA PHOSPHODIESTERASE

KW - GENOME

KW - TDP1gene knockout cells

KW - IMPACT

KW - VAPOR-PHASE

UR - http://www.scopus.com/inward/record.url?scp=85089133050&partnerID=8YFLogxK

U2 - 10.3390/molecules25153496

DO - 10.3390/molecules25153496

M3 - Article

C2 - 32751997

AN - SCOPUS:85089133050

VL - 25

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 15

M1 - 3496

ER -

ID: 24953716