Abstract
A series of heterocyclic compounds containing spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework have been synthesized and studied as potential antitumor agents. Antiproliferative activity of synthesized products was screened against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines. Spiroadducts with all cis bridge-protons of pyrrolo[3,4-a]pyrrolizine moiety were more active in all cases. Replacement of hydrogen atom of pyrrole moiety by either alkyl or aryl group leads to significant decreasement in activity of both formed cycloadducts. 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 induce apoptosis. Using confocal microscopy, we found that with synthesized products 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 screened compounds significantly reduced the number of cells with filopodium-like membrane protrusions (from 63 % in control cells to 29% after treatment) and decrease in cell motility. All obtained data make it possible to assume that spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework may be considered as a new promising pharmacophore unit for further screenings.
Highlights
Oncological diseases are one of the most common public health problems and the second leading cause of death after cardiovascular disease
We discovered that human cervical carcinoma (HeLa) cells after treatment with screened compounds significantly reduced the number of cells with filopodium-like membrane protrusions and decrease in cell motility
Replacement of hydrogen atom of pyrrole moiety by either alkyl or aryl group leads to significant decrease in activity of both formed cycloadducts
Summary
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. 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 originating from compounds of a new nature. Many of the most currently applicable (or that under clinical trials) anticancer drugs are either themselves compounds of natural origin, or designed based on naturally occurring compounds. All the compounds were evaluated for their antiproliferative activity as well as cell motility, morphological changes, cell cycle, cell death were evaluated for the most active products
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