TY - JOUR

T1 - Biological Evaluation of 3-Azaspiro[Bicyclo[3.1.0]Hexane-2,5′-Pyrimidines] as Potential Antitumor Agents

AU - Shmakov, Stanislav V.

AU - Latypova, Diana K.

AU - Shmakova, Tatiana V.

AU - Rubinshtein, Artem A.

AU - Chukin, Mark V.

AU - Zhuravskii, Sergei G.

AU - Knyazev, Nickolay A.

AU - Stepakov, Alexander V.

AU - Galagudza, Michael M.

AU - Boitsov, Vitali M.

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/9/15

Y1 - 2022/9/15

N2 - A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and African green monkey kidney epithelial (Vero) cell lines. The most effective among the screened compounds show IC50 in the range from 4.2 to 24.1 μM for all tested cell lines. The screened compounds have demonstrated a significant effect of the distribution of HeLa and CT26 cells across the cell cycle stage, with accumulation of cells in SubG1 phase and induced apoptosis. It was found, using a confocal microscopy, that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm of up to 90% of HeLa cells and up to 64% of CT26 cells after treatment with tested 3-azaspiro[bicyclo [3.1.0]hexane-2,5′-pyrimidines]. We discovered that the number of HeLa cells with filopodium-like membrane protrusions was reduced significantly (from 91% in control cells to 35%) after treatment with the most active compounds. A decrease in cell motility was also noticed. Preliminary in vivo experiments on the impact of the studied compounds on the dynamics of CT26 tumor growth in Balb/C mice were also performed.

AB - A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and African green monkey kidney epithelial (Vero) cell lines. The most effective among the screened compounds show IC50 in the range from 4.2 to 24.1 μM for all tested cell lines. The screened compounds have demonstrated a significant effect of the distribution of HeLa and CT26 cells across the cell cycle stage, with accumulation of cells in SubG1 phase and induced apoptosis. It was found, using a confocal microscopy, that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm of up to 90% of HeLa cells and up to 64% of CT26 cells after treatment with tested 3-azaspiro[bicyclo [3.1.0]hexane-2,5′-pyrimidines]. We discovered that the number of HeLa cells with filopodium-like membrane protrusions was reduced significantly (from 91% in control cells to 35%) after treatment with the most active compounds. A decrease in cell motility was also noticed. Preliminary in vivo experiments on the impact of the studied compounds on the dynamics of CT26 tumor growth in Balb/C mice were also performed.

KW - 3-azaspiro[bicyclo[3.1.0]hexane-2,5′-pyrimidines]

KW - alloxan-derived azomethine ylide

KW - antiproliferative activity

KW - cancer cell lines (K-562; HeLa; Jurkat; CT26; Vero)

KW - cell cycle

KW - cell death

KW - cell motility

KW - cyclopropenes

KW - in vitro and in vivo activity

KW - morphological changes (cytoskeleton)

KW - Carcinoma

KW - Cell Proliferation

KW - Chlorocebus aethiops

KW - Hexanes/pharmacology

KW - Humans

KW - Actins

KW - Pyrimidines/pharmacology

KW - Antineoplastic Agents/pharmacology

KW - Animals

KW - Cell Line, Tumor

KW - Mice

KW - HeLa Cells

KW - Apoptosis

KW - Drug Screening Assays, Antitumor

UR - http://www.scopus.com/inward/record.url?scp=85138390026&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/efca4745-d3cf-3362-bcd4-55f7dcfa67b6/

U2 - 10.3390/ijms231810759

DO - 10.3390/ijms231810759

M3 - Article

C2 - 36142688

AN - SCOPUS:85138390026

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 18

M1 - 10759

ER -