Novel mitochondria-targeted amphiphilic aminophosphonium salts and lipids nanoparticles: synthesis, antitumor activity and toxicity

Vladimir F. Mironov; Mudaris N. Dimukhametov; Andrey V. Nemtarev; Tatiana N. Pashirova; Olga V. Tsepaeva; Alexandra D. Voloshina; Alexandra B. Vyshtakalyuk; Igor A. Litvinov; Anna P. Lyubina; Anastasiia S. Sapunova; Dinara F. Abramova; Vladimir V. Zobov

doi:10.20944/preprints202309.1553.v1

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preprints.org > chemistry and materials science > medicinal chemistry > doi: 10.20944/preprints202309.1553.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Novel mitochondria-targeted amphiphilic aminophosphonium salts and lipids nanoparticles: synthesis, antitumor activity and toxicity

Vladimir F. Mironov

^* ,

Mudaris N. Dimukhametov

Andrey V. Nemtarev

Tatiana N. Pashirova

Olga V. Tsepaeva

Alexandra D. Voloshina

Alexandra B. Vyshtakalyuk

Igor A. Litvinov

Anna P. Lyubina

Anastasiia S. Sapunova

Dinara F. Abramova

Vladimir V. Zobov

Version 1 : Received: 21 September 2023 / Approved: 21 September 2023 / Online: 22 September 2023 (09:40:48 CEST)

A peer-reviewed article of this Preprint also exists.

Mironov, V.F.; Dimukhametov, M.N.; Nemtarev, A.V.; Pashirova, T.N.; Tsepaeva, O.V.; Voloshina, A.D.; Vyshtakalyuk, A.B.; Litvinov, I.A.; Lyubina, A.P.; Sapunova, A.S.; Abramova, D.F.; Zobov, V.V. Novel Mitochondria-Targeted Amphiphilic Aminophosphonium Salts and Lipids Nanoparticles: Synthesis, Antitumor Activity and Toxicity. Nanomaterials 2023, 13, 2840. Mironov, V.F.; Dimukhametov, M.N.; Nemtarev, A.V.; Pashirova, T.N.; Tsepaeva, O.V.; Voloshina, A.D.; Vyshtakalyuk, A.B.; Litvinov, I.A.; Lyubina, A.P.; Sapunova, A.S.; Abramova, D.F.; Zobov, V.V. Novel Mitochondria-Targeted Amphiphilic Aminophosphonium Salts and Lipids Nanoparticles: Synthesis, Antitumor Activity and Toxicity. Nanomaterials 2023, 13, 2840.

Abstract

The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylamino)(phenyl) phosphonium iodides (bromides) 1 containing one, two, or three diethylamino groups were obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions and high yields. The structure of compounds 1 was established by NMR and XRD. In vitro a high cytotoxicity against the lines M-Hela, HuTu 80, PC3, DU-145, PANC-1 and MCF-7 was found. Selectivity index are in the range of 0.06-4.0 M (SI 17-277) for the most active compounds. ROS production, mitochondrial localization and the process of cellular apoptosis were investigated. Decorated by 1 of lipid systems (liposomes and solid lipid nanoparticles) improve the cytotoxicity and a decrease in toxicity against normal cell lines. Compounds 1 induce apoptosis proceeding along the mitochondrial pathway. Aminophosphonium salts 1 also exhibit a high selective activity against the Gram-positive bacteria strains S. aureus 209P, B. segeus 8035, including methicillin-resistant strains of S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead compounds.

Keywords

aminophosphonium salt; liposome; solid lipid nanoparticle; anticancer activity; apoptosis; antimicrobial activity; hemolytic activity; acute toxicity.

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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