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Synthesis of Cationic and Ionizable Amphiphiles Based on Heminal Aminodiol as Potential siRNA Delivery Systems

https://doi.org/10.32362/2410-6593-2019-14-3-42-49

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Abstract

Research methods based on the use of RNA interference mechanisms are now included among the basic methods of molecular biology. Drugs based on siRNA are being developed for the treatment of cancer, infectious diseases and other pathologies that are associated with impaired Junctions of specific genes. One of the main problems of siRNA-based drug development is their efficient and safe delivery to target cells. Modern delivery strategies are based on the use of chemical compounds or biological carriers, such as viruses. Lipid nanoparticles (liposomal agents) are the most advanced platform among non-viral vectors for the delivery of gene materials into cells. In this paper, a scheme has been proposed and the synthesis of new cationic amphiphiles has been carried out as the basis for the means of delivering siRNA to target cells. Synthesized amphiphiles belong to two types of cationic lipids: with a permanently charged amino group in the form of a salt and with an ionizable polar block. Ionized amphiphiles are a new generation of cationic lipids that exhibit reduced toxicity and immunogenicity. They undergo ionization only in the acidic environment of endosomes during intracellular transport in the cytosol, which leads to the release of the encapsulated cargo. The structure of the target compounds is based on diethanolamine derivatives, which is a spacer between the hydrophobic block and the polar fragment. The hydrophobic block contains palmitoyl residues, and the polar one - ethylenediamine and 3-diethylaminopropylamine derivatives. The developed synthetic scheme is distinguished by the simplicity and versatility of the proposed approach, which allows it to be used in the preparation of a series of samples in preparative quantities necessary for the subsequent physicochemical and biochemical studies.

About the Authors

Z. G. Denieva
MIREA - Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Zaret G. Denieva  - Master of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

86, Vernadskogo pr., Moscow, 119571

Scopus Author ID 57203550055, ResearcherID T-5756-2019



U. A. Budanova
MIREA - Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Ulyana A. Budanova - Ph.D. (Chemistry), Assistant of Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry.

86, Vernadskogo pr., Moscow, 119571

Scopus Author ID 14622352500, ResearcherID E-1659-2014



Yu. L. Sebyakin
MIREA - Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Yury L. Sebyakin - D.Sc. (Chemistry), Professor, Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry.

86, Vernadskogo pr., Moscow, 119571

Scopus Author ID 6701455145, ResearcherID T-2835-2019



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Supplementary files

1. Scheme. 1. Synthesis of cationic (9) and ionized (11) lipid-like structures.
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For citation:


Denieva Z.G., Budanova U.A., Sebyakin Yu.L. Synthesis of Cationic and Ionizable Amphiphiles Based on Heminal Aminodiol as Potential siRNA Delivery Systems. Fine Chemical Technologies. 2019;14(3):42-49. (In Russ.) https://doi.org/10.32362/2410-6593-2019-14-3-42-49

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