Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids
Abstract
:1. Introduction
2. Materials and Methods
2.1. Differential Scanning Microcalorimetry of Lipid Phase Transitions
2.2. Preparation of Planar Lipid Bilayers and Recording of Current
2.3. Calcein Release from Unilamellar Lipid Vesicles
3. Results and Discussion
3.1. Effects of Pyrimidine Nucleoside Derivatives on Lipid Packing
3.2. Effects of Nucleoside Derivatives on Membrane Permeability
3.2.1. Phospholipid Bilayers
3.2.2. Lipid Bilayers Enriched with Specific Mycobacterial Lipids
- (1)
- Addition of mMA into POPG bilayers potentiated the disintegrating activity of all tested nucleoside derivatives and the pore-forming ability of compounds 2, 4, and 6; it also inhibited the induction of ion-permeable pores by the 5-alkyluridine compound 1;
- (2)
- Introduction of kMA into POPG membranes facilitated the disordering activity of derivatives 1, 6, 8, and 9 and the pore-forming ability of compounds 2, 4, and 6;
- (3)
- Inclusion of ThO into POPG bilayers led to an increase in the ability of 5-alkyluridines 1 and 4 to cause membrane collapse and form ion-permeable pores, as well as inhibit and potentiate the disintegrating action of compounds 8 and 9, respectively.
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviation
References
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Compound | LogP | POPC | POPG | ||||
---|---|---|---|---|---|---|---|
Ctr, μM | IFmax, % | Ctr, μM | Csc, μM | gsc, pS | IFmax, % | ||
1 | 1.92 | 355 ± 10 | 8 ± 4 | 220 ± 15 | 175 ± 10 | 5–40 | 47 ± 5 |
2 | 1.86 | 360 ± 15 | 5 ± 3 | 250 ± 10 | 140 ± 15 | 5–10 | 38 ± 7 |
3 | 2.26 | 375 ± 10 | 10 ± 3 | 240 ± 15 | 145 ± 10 | 5–50 | 26 ± 4 |
4 | 2.66 | 350 ± 25 | 18 ± 4 | 210 ± 10 | 150 ± 10 | 30–210 | 39 ± 3 |
5 | 3.14 | 375 ± 10 | 7 ± 3 | 275 ± 15 | – # | – # | 5 ± 3 |
6 | 3.93 | 405 ± 15 | 6 ± 2 | 280 ± 10 | – # | – # | 11 ± 4 |
7 | 3.02 | 340 ± 20 | 5 ± 3 | 295 ± 15 | – # | – # | 10 ± 5 |
8 | 4.58 | 355 ± 10 | 4 ± 2 | 350 ± 10 | – # | – # | 14 ± 3 |
9 | 4.00 | 380 ± 20 | 3 ± 1 | 340 ± 15 | – # | – # | 4 ± 2 |
POPG/mMA (80/20 mol%) | POPG/kMA (80/20 mol%) | POPG/ThO (80/20 mol%) | |||||||
---|---|---|---|---|---|---|---|---|---|
Compound | Ctr, μM | Csc, μM | gsc, pS | Ctr, μM | Csc, μM | gsc, pS | Ctr, μM | Csc, μM | gsc, pS |
1 | 80 ± 30 | – # | – # | 83 ± 28 | – # | – # | 20 ± 10 | 8 ± 3 | 5–24 |
2 | 105 ± 55 | 58 ± 32 | 10–40 | 250 ± 50 | 65 ± 35 | 5–100 | nt * | nt * | nt * |
4 | 105 ± 73 | 22 ± 12 | 5–20 | 300 ± 50 | 20 ± 3 | 5–50 | 23 ± 3 | 18 ± 5 | 5–50 |
6 | 16 ± 7 | 3 ± 1 | 5–100 | 33 ± 18 | 9 ± 2 | 5–70 | nt * | nt * | nt * |
8 | 21 ± 4 | – # | – # | 90 ± 7 | – # | – # | 525 ± 140 | – # | – # |
9 | 62 ± 10 | – # | – # | 44 ± 12 | – # | – # | 80 ± 25 | – # | – # |
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Ostroumova, O.S.; Efimova, S.S.; Zlodeeva, P.D.; Alexandrova, L.A.; Makarov, D.A.; Matyugina, E.S.; Sokhraneva, V.A.; Khandazhinskaya, A.L.; Kochetkov, S.N. Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids. Pharmaceutics 2024, 16, 1110. https://doi.org/10.3390/pharmaceutics16091110
Ostroumova OS, Efimova SS, Zlodeeva PD, Alexandrova LA, Makarov DA, Matyugina ES, Sokhraneva VA, Khandazhinskaya AL, Kochetkov SN. Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids. Pharmaceutics. 2024; 16(9):1110. https://doi.org/10.3390/pharmaceutics16091110
Chicago/Turabian StyleOstroumova, Olga S., Svetlana S. Efimova, Polina D. Zlodeeva, Liudmila A. Alexandrova, Dmitry A. Makarov, Elena S. Matyugina, Vera A. Sokhraneva, Anastasia L. Khandazhinskaya, and Sergey N. Kochetkov. 2024. "Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids" Pharmaceutics 16, no. 9: 1110. https://doi.org/10.3390/pharmaceutics16091110