TY - JOUR

T1 - Identification of spiro-fused [3-azabicyclo[3.1.0]hexane]oxindoles as potential antitumor agents

T2 - Initial in vitro evaluation of anti-proliferative effect and actin cytoskeleton transformation in 3t3 and 3t3-sv40 fibroblast

AU - Knyazev, Nickolay A.

AU - Shmakov, Stanislav V.

AU - Pechkovskaya, Sofya A.

AU - Filatov, Alexander S.

AU - Stepakov, Alexander V.

AU - Boitsov, Vitali M.

AU - Filatova, Natalia A.

N1 - Knyazev, N.A.; Shmakov, S.V.; Pechkovskaya, S.A.; Filatov, A.S.; Stepakov, A.V.; Boitsov, V.M.; Filatova, N.A. Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast. Int. J. Mol. Sci. 2021, 22, 8264. https://doi.org/10.3390/ijms22158264

PY - 2021/7/31

Y1 - 2021/7/31

N2 - Novel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (4a, 4b and 4c) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) analysis was performed on 4a–c compounds with promising antiproliferative activity, previously synthetized and screened against human erythroleukemic cell line K562 tumor cell line. Cytotoxicity of 4a–c against murine fibroblast 3T3 and SV-40 transformed murine fibroblast 3T3-SV40 cell lines were evaluated. The 4a and 4c compounds were cytotoxic against 3T3-SV40 cells in comparison with those of 3T3. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that with 4a and 4c treatment of 3T3 cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 82–97% of cells. The number of 3T3-SV40 cells with stress fibers increased to 7–30% against 2% in control. We discovered that transformed 3T3-SV40 cells after treatment with compounds 4a and 4c significantly reduced the number of cells with filopodium-like membrane protrusions (from 86 % in control cells to 6–18% after treatment), which indirectly suggests a decrease in cell motility. We can conclude that the studied compounds 4a and 4c have a cytostatic effect, which can lead to a decrease in the number of filopodium-like membrane protrusions.

AB - Novel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (4a, 4b and 4c) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) analysis was performed on 4a–c compounds with promising antiproliferative activity, previously synthetized and screened against human erythroleukemic cell line K562 tumor cell line. Cytotoxicity of 4a–c against murine fibroblast 3T3 and SV-40 transformed murine fibroblast 3T3-SV40 cell lines were evaluated. The 4a and 4c compounds were cytotoxic against 3T3-SV40 cells in comparison with those of 3T3. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that with 4a and 4c treatment of 3T3 cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 82–97% of cells. The number of 3T3-SV40 cells with stress fibers increased to 7–30% against 2% in control. We discovered that transformed 3T3-SV40 cells after treatment with compounds 4a and 4c significantly reduced the number of cells with filopodium-like membrane protrusions (from 86 % in control cells to 6–18% after treatment), which indirectly suggests a decrease in cell motility. We can conclude that the studied compounds 4a and 4c have a cytostatic effect, which can lead to a decrease in the number of filopodium-like membrane protrusions.

KW - 3-spiro[azabicyclo[3.1.0]hexane]oxindoles

KW - 3T3

KW - 3T3-SV40

KW - Actin

KW - ADMET analysis

KW - Cell cycle

KW - Cytoskeleton

KW - Metastasis

KW - Tumor cells

KW - DRUG

KW - AZOMETHINE YLIDES

KW - 3-spiro[azabicyclo[3

KW - CYCLOPROPENES

KW - SPIROOXINDOLES

KW - INVASION

KW - metastasis

KW - tumor cells

KW - 0]hexane]oxindoles

KW - CELLS

KW - cytoskeleton

KW - cell cycle

KW - ONE-POT

KW - PREDICTION

KW - 1

KW - actin

KW - 3-COMPONENT 1,3-DIPOLAR CYCLOADDITION

UR - http://www.scopus.com/inward/record.url?scp=85111433268&partnerID=8YFLogxK

U2 - 10.3390/ijms22158264

DO - 10.3390/ijms22158264

M3 - Article

C2 - 34361029

AN - SCOPUS:85111433268

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 15

M1 - 8264

ER -