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

Abstract

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.

Design, synthesis, pharmacological evaluation, and in silico studies of the activity of novel spiro pyrrolo[3,4-d]pyrimidine derivatives

“… 64 Azaspiro compounds were evaluated biologically, and tested as potential antitumor agents. 65 They affect different cell cycle stages, and granular actin diffusion through the cytoplasm was observed using confocal microscopy. Other compounds containing azaspiro rings exhibited a potent kinase inhibitor activity.…”

[3+2] Cycloaddition of N‐benzylazomethine Methylide with Various Arylidene‐Azolones

“…Hydantoin core is present in a number of spirocyclic drugs, such as Fidarestat, [17,30] Hydantocidin [31] and advanced drug candidates, e. g. BMS-587101 and BMS-688521. [14,15] Preparation of heteroanalogs would provide vast opportunities in further drug design.…”

“…Herein, we tested a number of different moieties, containing sulfur such as thiohydantoins, rhodanines and their derivatives which undergoes the cycloaddition reaction and its stereoselectivity (Scheme 2). Hydantoin core is present in a number of spirocyclic drugs, such as Fidarestat, [17,30] Hydantocidin [31] and advanced drug candidates, e. g. BMS‐587101 and BMS‐688521 [14,15] . Preparation of heteroanalogs would provide vast opportunities in further drug design.…”

“…In particular, various spirocyclic derivatives incorporating five‐membered heterocyclic core are of interest, since their synthetic and natural analogs exhibit a wide range of pharmacological activities, including antimicrobial, antiviral, fungicidal, antidiabetic, anticonvulsant, antitumor and other effects (Scheme 1). [8–18] …”

“…[6,7] In particular, various spirocyclic derivatives incorporating five-membered heterocyclic core are of interest, since their synthetic and natural analogs exhibit a wide range of pharmacological activities, including antimicrobial, antiviral, fungicidal, antidiabetic, anticonvulsant, antitumor and other effects (Scheme 1). [8][9][10][11][12][13][14][15][16][17][18] Many methods have been developed for the synthesis of such substances. Among all of them, cycloaddition reactions occupy an important method.…”