Pentacyclic Triterpenoids-Based Ionic Compounds: Synthesis, Study of Structure-Antitumor Activity Relationship, Effects on Mitochondria and Activation of Signaling Pathways of Proliferation, Genome Reparation and Early Apoptosis

Simple Summary The search for new, effective and low-toxicity anticancer drugs is one of the most important tasks of modern medicinal chemistry. Pentacyclic triterpenoids constitute an important class of biologically active compounds with a wide range of biological and pharmacological activities. These compounds are of particular interest due to their antitumor and antiviral properties. Triterpenoids exhibit low toxicity to animals even at high concentrations, but their relatively low potential for biological action, low water solubility and unfavorable absorption and metabolism parameters are a serious obstacle to the use of these substances in clinical practice. In the framework of the presented work, we synthesize a series of ionic compounds based on betulinic, ursolic and oleanolic acids, which could, in our view, improve the solubility of these compounds and their permeability through biological membranes. The present research paper details the synthesis of novel ionic compounds based on triterpene acids (betulinic, oleanolic and ursolic), with these acids acting both as anions and connected through a spacer with various nitrogen-containing compounds (pyridine, piperidine, morpholine, pyrrolidine, triethylamine and dimethylethanolamine) and acting as a cation. Based on the latter, a large number of ionic compounds with various counterions (BF4-, SbF6-, PF6-, CH3COO-, C6H5SO3-, m-C6H4(OH)COO- and CH3CH(OH)COO-) have been synthesized. We studied the cytotoxicity of the synthesized compounds on the example of various tumor (Jurkat, K562, U937, HL60, A2780) and conditionally normal (HEK293) cell lines. IC50 was determined, and the influence of the structure and nature of the anion and cation on the antitumor activity was specified. Intracellular signaling, apoptosis induction and effects of the most active ionic compounds on the cell cycle and mitochondria have been discussed by applying modern methods of multiparametric enzyme immunoassay and flow cytometry.

Automated summary

The search for new, effective and low-toxicity anticancer drugs is of utmost importance in modern medicinal chemistry. Pentacyclic triterpenoids are a class of biologically active compounds with diverse biological and pharmacological activities, particularly in terms of their antitumor and antiviral properties. However, their low potential for biological action, low water solubility, and unfavorable absorption and metabolism parameters pose significant challenges in their clinical use. In this study, we synthesized a series of ionic compounds based on betulinic, ursolic, and oleanolic acids to enhance the solubility and permeability of these compounds through biological membranes.