Еvaluation of antitumor activity of some 4-aminopiperidine derivatives — low molecular weight Hsp70 inhibitors — on transplantable mouse tumors

Aldobaev VN1, Mikhina LV1, Present MA2
About authors

1 Research Centre for Toxicology and Hygienic Regulation of Biopreparations of FMBA, Serpukhov, Russia

2 Zelinsky Institute of Organic Chemistry, Moscow, Russia

Correspondence should be addressed: Vladimir N. Aldobaev
Lenina, 102A, pos. Bolshevik, Moscow oblast,142283; ur.oibcixot@veabodla

About paper

Funding: the study was carried out under the State Assignment for FMBA №

Author contribution: Aldobaev VN planned the experiment, summarized its results and wrote this manuscript; Mikhina LV carried out the experiment in animal models; Present MA synthesized the tested compounds.

Compliance with ethical standards: the study was approved by the Ethics Committee of the Research Centre for Toxicology and Hygienic Regulation of Biopreparations (Protocol № 695 dated November 12, 2019). Housing conditions met the requirements of Sanitary Regulations (Sanitary and Epidemiological Requirements for Design, Equipment and Maintenance of Vivarium Facilities) and the guidelines provided in the Guide for Care and Use of Laboratory Animals (ILAR publication, 1996, National Academy Press, USA).

Received: 2021-02-13 Accepted: 2021-03-12 Published online: 2021-03-21

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.

Keywords: heat shock proteins, Hsp70 inhibitors, transplantable tumor, L1210 leukemia, B16 melanoma