Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure

We propose a nucleic acids dilution-induced assembly (NADIA) method for the preparation of lipid nanoparticles. In the conventional method, water-soluble polymers such as nucleic acids and proteins are mixed in the aqueous phase. In contrast, the NADIA method, in which self-assembly is triggered upon dilution, requires dispersion in an alcohol phase without precipitation. We then investigated several alcohols and discovered that propylene glycol combined with sodium chloride enabled the dispersion of plasmid DNA and protamine sulfate in the alcohol phase. The streamlined characteristics of the NADIA method enable the preparation of extracellular vesicles-mimicking lipid nanoparticles (ELNPs). Among the mixing methods using a micropipette, a syringe pump, and a microfluidic device, the lattermost was the best for decreasing batch-to-batch differences in size, polydispersity index, and transfection efficiency in HepG2 cells. Although ELNPs possessed negative ζ-potentials and did not have surface antigens, their transfection efficiency was comparable to that of cationic lipoplexes. We observed that lipid raft-mediated endocytosis and macropinocytosis contributed to the transfection of ELNPs. Our strategy may overcome the hurdles linked to supply and quality owing to the low abundance and heterogeneity in cell-based extracellular vesicles production, making it a reliable and scalable method for the pharmaceutical manufacture of such complex formulations.

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Synthesis and biological properties of small molecules — ligands of non-canonical DNA and RNA structures

Abramovich,

Zaikina,

Barskaya

et al. 2024

RUSS CHEM REV

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Nucleic acids are important targets for many anticancer drugs. Apart from the canonical B-DNA double helix, DNA forms a number of non-canonical structures (G-quadruplexes, i-motifs, hairpins, triplexes, etc.), which play an important role in the regulation of biological processes. Binding to non-canonical DNA structures occurs mainly by π–π-stacking. Therefore, aromatic and heteroaromatic compounds, in particular fused poly-aromatic compounds (acridines, anthraquinones, carbazoles), porphyrins, benzothiazoles, benzimidazoles, pyridines, and quinolines, as well as their complexes are used as ligands for secondary structures. These ligands should possess not only high selectivity to non-canonical structures compared to double-stranded DNA, but also relatively high solubility and penetration through cell membranes. This review summarizes the achievements of 2020–2024 in the synthesis and biological studies of (hetero)arenes (acridines, anthraquinones, benzazoles, xanthones, porphyrins) and coordination compounds that have exhibited anticancer activity as a result of binding to non-canonical DNA or RNA structures. Ligands of various types of non-canonical nucleic acid structures (G-quadruplexes, i-motifs, triplexes, hairpins) are considered and their cytotoxic activity and structure–property relationships are compared. <br> The bibliography includes 166 references.

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Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure

Cited by 3 publications

References 48 publications

i-Motif DNA: identification, formation, and cellular functions

i-Motif DNA: identification, formation, and cellular functions

One-Step Formation Method of Plasmid DNA-Loaded, Extracellular Vesicles-Mimicking Lipid Nanoparticles Based on Nucleic Acids Dilution-Induced Assembly

Synthesis and biological properties of small molecules — ligands of non-canonical DNA and RNA structures

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