Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity.

Autor: Mikhnovets IE; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Holoubek J; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic.; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, CZ-370 05 České Budějovice, Czech Republic.; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-625 00 Brno, Czech Republic., Panina IS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Kotouček J; Department of Pharmacology and Toxicology, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic., Gvozdev DA; Department of Biology, Lomonosov Moscow State University, Leninskie Gory 1-12, 119234 Moscow, Russia., Chumakov SP; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Krasilnikov MS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia., Zhitlov MY; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.; Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia., Gulyak EL; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Chistov AA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Nikitin TD; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Korshun VA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Efremov RG; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Alferova VA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia., Růžek D; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic.; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, CZ-370 05 České Budějovice, Czech Republic.; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-625 00 Brno, Czech Republic., Eyer L; Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic.; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, CZ-370 05 České Budějovice, Czech Republic.; Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-625 00 Brno, Czech Republic., Ustinov AV; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Nov 18; Vol. 24 (22). Date of Electronic Publication: 2023 Nov 18.
DOI: 10.3390/ijms242216483
Abstrakt: Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel-Crafts acylation and Wolff-Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents ( n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen.
Databáze: MEDLINE
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