Identification of Spiro-Fused Pyrrolo[3,4-a]pyrrolizines and Tryptanthrines as Potential Antitumor Agents: Synthesis and In Vitro Evaluation.

Diana K Latypova,Vitali M Boitsov,Alexander V Stepakov,Nickolay A Knyazev,Alexander S Filatov,Sofya A Pechkovskaya,Stanislav V Shmakov

doi:10.3390/ijms222111997

Abstract

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.

Highlights

Oncological diseases are one of the most common public health problems and the second leading cause of death after cardiovascular disease
Such formed ylides were used for the synthesis of complex alkaloid-like compounds with spiro-fused indolo[2,1-b]quinazoline and cyclopropa[a]pyrrolizine or 3-azabicyclo[3.1.0]hexane moieties via one-pot, three-component 1,3dipolar cycloaddition reactions of various cyclopropenes with in situ generated tryptanthrinderived azomethine ylides [35]
We have established the ability of heterocyclic compounds containing spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework to reduce the viability of both human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines

Summary

Introduction

Oncological diseases are one of the most common public health problems and the second leading cause of death after cardiovascular disease. Increased drug resistance and the emergence of tumor resistance as well as severe side-effects of chemotherapeutic agents reduce the clinical efficacy of currently used anticancer drugs and treatments. Multi-drug resistance of malignant tumors is one of the main causes for their clinical progression. Despite the increasing use of targeted drugs and methods of immunotherapy of oncological diseases, the development of cytostatic agents remains an important challenge for the treatment of cancer. The emergence of tumor resistance requires the creation of cytostatics that are not just derivatives of “classical” drugs, but originate from compounds of a new nature. It is worth noting that the ability of cytostatics to influence the activity of the immune system makes it possible to use them for the treatment of autoimmune diseases

Methods

Results

Conclusion