Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed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
ORCID logo ,
Tatiana N. Pashirova
ORCID logo ,
Olga V. Tsepaeva
,
Alexandra D. Voloshina
ORCID logo ,
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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