TY - JOUR

T1 - Identification of spiro-fused pyrrolo[3,4-a]pyrrolizines and tryptanthrines as potential antitumor agents

T2 - Synthesis and in vitro evaluation

AU - Latypova, Diana K.

AU - Shmakov, Stanislav V.

AU - Pechkovskaya, Sofya A.

AU - Filatov, Alexander S.

AU - Stepakov, Alexander V.

AU - Knyazev, Nickolay A.

AU - Boitsov, Vitali M.

N1 - Latypova, D.K.; Shmakov, S.V.; Pechkovskaya, S.A.; Filatov, A.S.; Stepakov, A.V.; Knyazev, N.A.; Boitsov, V.M. Identification of Spiro-Fused Pyrrolo[3,4-a]pyrrolizines and Tryptanthrines as Potential Antitumor Agents: Synthesis and In Vitro Evaluation. Int. J. Mol. Sci. 2021, 22, 11997. https://doi.org/10.3390/ijms222111997

PY - 2021/11/5

Y1 - 2021/11/5

N2 - A series of heterocyclic compounds containing a spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework have been synthesized and studied as potential antitumor agents. Cytotoxicity of products was screened against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines. Among the screened compounds. 4a, 4b and 5a were active against human erythroleukemia (K562) cell line, while 4a and 5a were active against cervical carcinoma (HeLa) cell line. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G2/M phase and induced apoptosis. Using confocal microscopy, we found that with 4a and 5a treatment of HeLa cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 76–91% of cells. We discovered that HeLa cells after treatment with compounds 4a and 5a significantly reduced the number of cells with filopodium-like membrane protrusions (from 63 % in control cells to 29% after treatment) and a decrease in cell motility.

AB - A series of heterocyclic compounds containing a spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework have been synthesized and studied as potential antitumor agents. Cytotoxicity of products was screened against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines. Among the screened compounds. 4a, 4b and 5a were active against human erythroleukemia (K562) cell line, while 4a and 5a were active against cervical carcinoma (HeLa) cell line. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G2/M phase and induced apoptosis. Using confocal microscopy, we found that with 4a and 5a treatment of HeLa cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 76–91% of cells. We discovered that HeLa cells after treatment with compounds 4a and 5a significantly reduced the number of cells with filopodium-like membrane protrusions (from 63 % in control cells to 29% after treatment) and a decrease in cell motility.

KW - 1,3-dipolar cycloaddition

KW - Antiproliferative activity

KW - Cell cycle

KW - Cell death

KW - Cell motility

KW - Morphological changes (cytoskeleton)

KW - One-pot synthesis

KW - Pyrrolo[3,4-a]pyrrolizine

KW - Tryptanthrin-derived azomethine ylide

KW - Tumor cells

KW - DESIGN

KW - ACTIVE-SITE

KW - AZOMETHINE YLIDES

KW - morphological changes (cytoskeleton)

KW - CYCLOPROPENES

KW - antiproliferative activity

KW - tumor cells

KW - one-pot synthesis

KW - DERIVATIVES

KW - cell death

KW - cell cycle

KW - ANALOGS

KW - PYRROLIZIDINE ALKALOIDS

KW - ONE-POT

KW - pyrrolo[3,4-a]pyrrolizine

KW - cell motility

KW - 3-COMPONENT 1,3-DIPOLAR CYCLOADDITION

KW - tryptanthrin-derived azomethine ylide

KW - ANTIMICROBIAL ACTIVITY

UR - http://www.scopus.com/inward/record.url?scp=85118387053&partnerID=8YFLogxK

U2 - 10.3390/ijms222111997

DO - 10.3390/ijms222111997

M3 - Article

AN - SCOPUS:85118387053

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 21

M1 - 11997

ER -