The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. Spirocyclic compounds were obtained in moderate to good yields, albeit with poor diastereoselectivity. Density functional theory calculations were performed to obtain an insight into the mechanism of the 1,3-dipolar cycloaddition of 11H-benzo[4,5]imidazo[1,2-a]indol-11-one-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some of the obtained cycloadducts against the human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.

One of the promising directions in 1,3-dipolar cycloaddition is the implementation of these reactions under organocatalysis conditions, which makes it possible to achieve not only high products yields, but also complete stereocontrol of the process. The presented review analyzes data published over the past 5 years according to the types of 1,3-dipoles involved into reactions. In a number of cases, the mechanisms of 1,3-dipolar cycloaddition reactions occurring in the presence of organocatalysts are discussed in detail.

A three-component organocatalytic reaction of 1,3-dipolar cycloaddition between the in situ generated azomethine ylides and 3-substituted 1,2-diphenylcyclopropenes is described. The azomethine ylides have been generated via condensation of aromatic compounds (such as isatins and acenaphthenequinone) with benzylamines. The reaction has afforded derivatives of 3-azabicyclo[3.1.0]hexane, spiro-fused with the fragments of 2-oxindole and acenaphthylene-1(2H)-one. The cycloadducts have been obtained with yield up to 91%, mainly as individual diastereomers. The influence of bifunctional squaramide-based organocatalysts on the course of these three-component reactions has been investigated. Antiproliferative activity of selected synthesized compounds with respect to the human erythromyelosis (K562) and melanoma (Sk-mel-2) cell lines has been assessed in vitro by means of MTS analysis.

A series of 3-azabicyclo[3.1.0]hexanes and cyclopropa[a]pyrrolizidines spiro-fused to acenaphthylene-1(2H)-one and aceanthrylene-1(2H)-one frameworks have been studied for their in vitro antiproliferative activity against human erythroleukemia (K562), cervical carcinoma (HeLa), melanoma (Sk-mel-2), osteosarcoma (U2OS), as well as murine melanoma (B16) cell lines. Using confocal microscopy, it was found that cultivation with the tested spiro-fused compounds led to the disappearance of stress fibers (granular actin was distributed diffusely in the cytoplasm in up to 56% of treated cells) and decrease in filopodia-like deformations (up to 69% after cultivation), which indirectly suggests a decrease in cell motility. The human melanoma cell line scratch test showed that these cells lose their ability to move after cultivation with the tested spiro-fused compounds and do not fill the scratched strip. This was also supported by docking simulations with actin-related targets (PDB ID: 8DNH, 2Q1N). Using flow cytometry, the impact on the mitochondrial membrane potential showed that the tested compounds led to a significant increase in the number of cells with decreased mitochondrial membrane potential from 10% for the control up to 55–80% for the cyclopropa[a]pyrrolizidine adducts. The obtained results support the antitumor effect of the tested spiro-compounds and encourage the extension of the study in order to improve their anticancer activity as well as reduce their toxicological risks.

The reaction of 1,3-dipolar cycloaddition of a stable azomethine ylide formed from ninhydrin and L-proline to activated acetylenic phosphonates was studied. It was found that the reactions proceed under mild conditions with high regioselectivity to form cycloadducts with a spiro[indeno-2,3′-pyrrolizine]-1,3-dione backbone.