mesЭкстремальная биомедицинаExtreme Medicine3033-89643033-8972Centre for Strategic Planning of the Federal Medical and Biological Agency10.47183/mes.2021.009mes-104Research ArticleОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕORIGINAL RESEARCHОценка противоопухолевой активности ряда производных 4-аминопиперидина, низкомолекулярных ингибиторов Hsp70, на перевиваемых опухолях мышейЕvaluation of antitumor activity of some 4-aminopiperidine derivatives — low molecular weight Hsp70 inhibitors — on transplantable mouse tumorsАлдобаевВ. Н.AldobaevV. N.

Владимир Николаевич Алдобаев

ул. Ленина, д. 102А, пос. Большевик, Московская область, 142283

Vladimir N. Aldobaev

Lenina, 102A, pos. Bolshevik, Moscow oblast,142283

aldobaev@toxicbio.ruМихинаЛ. В.MikhinaL. V.

Серпухов

Serpukhov

ПрезентМ. А.PresentM. A.

Москва

Moscow

Научно-исследовательский центр токсикологии и гигиенической регламентации биопрепаратов Федерального медико-биологического агентстваРоссияResearch Centre for Toxicology and Hygienic Regulation of Biopreparations of FMBARussian FederationИнститут органической химии имени Н. Д. ЗелинскогоРоссияZelinsky Institute of Organic ChemistryRussian Federation2021241020242312431Copyright © Алдобаев В.Н., Михина Л.В., Презент М.А., 20242024Алдобаев В.Н., Михина Л.В., Презент М.А.Aldobaev V.N., Mikhina L.V., Present M.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.extrememedicine.ru/jour/article/view/104

Применение низкомолекулярных агентов, мишенью которых являются молекулярные шапероны Hsp90 и Hsp70, стало основой для целого направления в терапии новообразований. В 2020 г. была проведена сравнительная оценка противоопухолевой активности на моделях in vivo трех производных 4-аминопиперидина ингибиторов Hsp70: N-(2-хлоробензил)-N-этил-1-(2-(метилтио)пиримидин-4-ил)пиперидин-4-амина (№ 1); 4-((метил(1- (2-(метилтио)пиримидин-4-ил)пиперидин-4-ил)амино)метил) бензонитрила (№ 2); N-(2,6-дихлорбензил)-1-(1-(2-(этилтио)пиримидин-4-ил)пиперидин-4-ил)- N-метилметанамина (№ 3). Целью работы было провести сравнительные испытания эффективности производных 4-аминопиперидина in vivo на перевиваемых опухолях мышей. Противоопухолевую активность исследуемых веществ изучали на моделях лимфоидной лейкемии L1210 и меланомы B16. Субстанции № 2 и 3 продемонстрировали высокую статистически значимую (р = 0,05) активность в случае комбинированной терапии с циклофосфамидом для лейкоза L1210 (увеличение продолжительности жизни — 80–82%) и для меланомы В16 (торможение роста опухоли — 98–99,7%). В случае L1210 вещества № 2 и 3 в комбинации с цитостатиком попали в низшую категорию перспективности «+» для модельных лейкозов животных. В случае В16 вещества № 1–3 в комбинации с цитостатиком попадали либо в низшую категорию перспективности «+», либо в категорию «++» для модельных солидных опухолей животных. Испытанные дозировки субстанций продемонстрировали обещающие результаты лечения в комбинации с циклофосфамидом на перевиваемых опухолях лимфоидной лейкемии L1210 и меланомы B16 мышей. Полученные эффекты подтверждают перспективность применения низкомолекулярных ингибиторов Hsp70 в составе комбинированной химиотерапии в онкологии.

Low molecular weight compounds targeting chaperone proteins Hsp90 and Hsp70 have opened up a new avenue in the therapy of neoplasms. In 2020, we tested 3 Hsp70 inhibitors from the class of 4-aminopiperidine derivatives for their antitumor activity on in vivo models. The list of the tested compounds included N-(2-chlorobenzyl)-N-ethyl-1-(2-(methylthio)pyrimidin-4-yl)piperidin-4-amine (compound 1), 4-((methyl(1-(2-(methylthio)pyrimidin-4-yl) piperidin-4-yl)amino)methyl) benzonitrile (compound 2) and N-(2,6- dichlorobenzyl)-1-(1-(2-(ethylthio)pyrimidin-4-yl)piperidin-4-yl)-N-methylmethaneamine (compound 3). The aim of this study was to compare the efficacy of 4-aminopiperidine derivatives in vivo using the models of transplantable murine L1210 lymphocytic leukemia and B16 melanoma. Compounds 2 and 3 used in combination with cyclophosphamide exhibited high cytotoxic activity (р = 0.05) against L1210 leukemia (an 80-82% increase in survival time) and B16 melanoma (98-99.7% tumor growth delay). For L1210 lymphocytic leukemia, compounds 2 and 3 used in combination with cyclophosphamide fell into the low (+) therapeutic potential category. For B16 melanoma, compounds 1, 2 and 3 used in combination with cyclophosphamide fell into either low (+) or moderate (++) therapeutic potential categories. On the whole, the tested doses of the compounds used in combination with cyclophosphamide hold promise for the therapy of L1210 leukemia and B16 melanoma in mouse models. Our findings confirm the potential of low molecular weight Hsp70 inhibitors for combination chemotherapy against cancer.

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The authors declare that there are no conflicts of interest present.