Abstract
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.
Highlights
Low molecular weight compounds targeting chaperone proteins Hsp90 and Hsp70 have opened up a new avenue in the therapy of neoplasms
Prior to evaluating the efficacy of N-(2-chlorobenzyl)-N-ethyl-1(2-(methylthio)pyrimidin-4-yl)piperidin-4-amine, 4-((methyl(1-(2-(methylthio)pyrimidin-4-yl) piperidin-4yl)amino)methyl) benzonitrile and N-(2,6dichlorobenzyl)-1-(1-(2-(ethylthio)pyrimidin-4-yl)piperidin-4yl)-N-methylmethaneamine, we conducted a series of preliminary experiments to determine their maximum tolerated dose (MTD, single intraperitoneal injection) for BDF1 (C57Bl/6 × DBA/2) hybrid mice
The aim of the study was achieved: we successfully evaluated the Hsp70-inhibiting potential of 4-aminopiperidine derivatives using murine models of transplantable L1210 lymphocytic leukemia and solid B16 melanoma
Summary
Low molecular weight compounds targeting chaperone proteins Hsp and Hsp have opened up a new avenue in the therapy of neoplasms. In 2020, we tested 3 Hsp inhibitors from the class of 4-aminopiperidine derivatives for their antitumor activity on in vivo models. 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. 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. 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. Полученные эффекты подтверждают перспективность применения низкомолекулярных ингибиторов Hsp в составе комбинированной химиотерапии в онкологии
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