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Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments. / Mozhaitsev, Evgenii S.; Zakharenko, Alexandra L.; Suslov, Evgeniy V. et al.

In: Anti-Cancer Agents in Medicinal Chemistry, Vol. 19, No. 4, 01.01.2019, p. 463-472.

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

Harvard

Mozhaitsev, ES, Zakharenko, AL, Suslov, EV, Korchagina, DV, Zakharova, OD, Vasil’eva, IA, Chepanova, AA, Black, E, Patel, J, Chand, R, Reynisson, J, Leung, IKH, Volcho, KP, Salakhutdinov, NF & Lavrik, OI 2019, 'Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments', Anti-Cancer Agents in Medicinal Chemistry, vol. 19, no. 4, pp. 463-472. https://doi.org/10.2174/1871520619666181207094243

APA

Mozhaitsev, E. S., Zakharenko, A. L., Suslov, E. V., Korchagina, D. V., Zakharova, O. D., Vasil’eva, I. A., Chepanova, A. A., Black, E., Patel, J., Chand, R., Reynisson, J., Leung, I. K. H., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2019). Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments. Anti-Cancer Agents in Medicinal Chemistry, 19(4), 463-472. https://doi.org/10.2174/1871520619666181207094243

Vancouver

Mozhaitsev ES, Zakharenko AL, Suslov EV, Korchagina DV, Zakharova OD, Vasil’eva IA et al. Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments. Anti-Cancer Agents in Medicinal Chemistry. 2019 Jan 1;19(4):463-472. doi: 10.2174/1871520619666181207094243

Author

Mozhaitsev, Evgenii S. ; Zakharenko, Alexandra L. ; Suslov, Evgeniy V. et al. / Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments. In: Anti-Cancer Agents in Medicinal Chemistry. 2019 ; Vol. 19, No. 4. pp. 463-472.

BibTeX

@article{1652ea9595134481a943776062c03f80,
title = "Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments",
abstract = "Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Method: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.",
keywords = "3,7-dimethyloctanol, Chemical space, Citronellol, Cytotoxicity, Esters, Inhibitors, Molecular modelling, Terpene, inhibitors, esters, EMPIRICAL SCORING FUNCTIONS, TOPOISOMERASE-I, 3,7-dimethy loctanol, TOPOTECAN, BIOLOGICAL EVALUATION, chemical space, cytotoxicity, ASSAY, molecular modelling, PHOSPHODIESTERASE 1 TDP1, terpene, IDENTIFICATION, PROTEIN-LIGAND DOCKING, COLORECTAL-CANCER, BINDING",
author = "Mozhaitsev, {Evgenii S.} and Zakharenko, {Alexandra L.} and Suslov, {Evgeniy V.} and Korchagina, {Dina V.} and Zakharova, {Olga D.} and Vasil{\textquoteright}eva, {Inna A.} and Chepanova, {Arina A.} and Ellena Black and Jinal Patel and Raina Chand and J{\'o}hannes Reynisson and Leung, {Ivanhoe K.H.} and Volcho, {Konstantin P.} and Salakhutdinov, {Nariman F.} and Lavrik, {Olga I.}",
note = "Copyright{\textcopyright} Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.",
year = "2019",
month = jan,
day = "1",
doi = "10.2174/1871520619666181207094243",
language = "English",
volume = "19",
pages = "463--472",
journal = "Anti-Cancer Agents in Medicinal Chemistry",
issn = "1871-5206",
publisher = "Bentham Science Publishers B.V.",
number = "4",

}

RIS

TY - JOUR

T1 - Novel inhibitors of DNA repair enzyme TDP1 combining monoterpenoid and adamantane fragments

AU - Mozhaitsev, Evgenii S.

AU - Zakharenko, Alexandra L.

AU - Suslov, Evgeniy V.

AU - Korchagina, Dina V.

AU - Zakharova, Olga D.

AU - Vasil’eva, Inna A.

AU - Chepanova, Arina A.

AU - Black, Ellena

AU - Patel, Jinal

AU - Chand, Raina

AU - Reynisson, Jóhannes

AU - Leung, Ivanhoe K.H.

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

AU - Lavrik, Olga I.

N1 - Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Method: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

AB - Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. Method: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

KW - 3,7-dimethyloctanol

KW - Chemical space

KW - Citronellol

KW - Cytotoxicity

KW - Esters

KW - Inhibitors

KW - Molecular modelling

KW - Terpene

KW - inhibitors

KW - esters

KW - EMPIRICAL SCORING FUNCTIONS

KW - TOPOISOMERASE-I

KW - 3,7-dimethy loctanol

KW - TOPOTECAN

KW - BIOLOGICAL EVALUATION

KW - chemical space

KW - cytotoxicity

KW - ASSAY

KW - molecular modelling

KW - PHOSPHODIESTERASE 1 TDP1

KW - terpene

KW - IDENTIFICATION

KW - PROTEIN-LIGAND DOCKING

KW - COLORECTAL-CANCER

KW - BINDING

UR - http://www.scopus.com/inward/record.url?scp=85054071064&partnerID=8YFLogxK

U2 - 10.2174/1871520619666181207094243

DO - 10.2174/1871520619666181207094243

M3 - Article

C2 - 30523770

AN - SCOPUS:85054071064

VL - 19

SP - 463

EP - 472

JO - Anti-Cancer Agents in Medicinal Chemistry

JF - Anti-Cancer Agents in Medicinal Chemistry

SN - 1871-5206

IS - 4

ER -

ID: 21044423