New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Cytotoxicity and Antiretroviral Activity
2.3. Molecular Docking Study
2.4. Molecular Dynamics Simulations
3. Materials and Method
3.1. Biological Activity
3.1.1. Cytotoxicity
3.1.2. Anti-HIV Activity
3.2. Synthesis
3.2.1. Synthesis of 3-Acetyl-30-Diethoxyphosphorylbetulin 5
3.2.2. General Procedures for Oxidation with the Jones Reagent
3.2.3. General Procedures for the Sodium Borohydride Reduction (Synthesis of Compounds 9 and 10)
3.2.4. Synthesis of 30-Diethoxyphosphorylbetulinic Acid 11
3.2.5. General Method of Synthesis 3-Carboxyacyl Derivatives 12a–c, 13a–c and 14a–c
3.3. Molecular Docking Study
3.4. Molecular Dynamic Simulations
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BVM | Bevirimat |
EC50 | Half maximal effective concentration—the concentration of a compound at which 50% of the Population exhibit a response |
TI | Therapeutic index |
CC50 | Cytotoxicity concentration of 50%—concentration required for the reduction of cell viability by 50% |
IC50 | Half maximal inhibitory concentration—the concentration of a compound required to inhibit 50% of a specific biological or biochemical function |
HSV | Herpes simplex virus |
HBV | Hepatitis B virus |
ELISA | Enzyme-linked immunosorbent assay |
MTT | 3-(4,5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide |
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Compound | Solvent | Temperature (Temp.) [°C] | Time [h] | Yield [%] |
---|---|---|---|---|
4 | KOH in CH3CH2OH | Reflux | 2 | 61 |
5 | NaOH in CH3OH/H2O/THF | Room temp. | 0.5 | 61 |
11 | NaOH in CH3OH/H2O/THF | Room temp. | 24 | 66 |
Compound | CC50 (μM) | IC50 (μM) | TI | |
---|---|---|---|---|
bevirimat betulinic acid betulin | 29 ± 2.43 | 0.03 ± 0.009 | 967 | |
5 ± 2.44 | NO | - | ||
46±3.01 | NO | - | ||
9 | 18 ± 1.79 | NO | - | |
10 | 80 ± 1.3 | >10 | <8 | |
11 | >42 | >10 | >4 | |
12a | 52 ± 1.07 | 1 ± 0.33 | 52 | |
12b | 28 ± 1.64 | 0.6 ± 0.04 | 47 | |
12c | 64 ± 1.84 | 4 ± 1.65 | 16 | |
13a | >68 | 2 ± 0.72 | >35 | |
13b | >68 | 8.8 ± 1.70 | >8 | |
13c | >68 | >10 | >7 | |
14a | >68 | 0.02 ± 0.01 | 3450 | |
14b | >68 | 0.9 ± 0.12 | >75 | |
14c | >68 | 1 ± 0.17 | >68 |
Compound | 12a | 12b | 12c | 13a | 13b | 13c | 14a | 14b | 14c | BVM |
---|---|---|---|---|---|---|---|---|---|---|
Binding energy ΔG [kcal/mol] | −6.13 | −5.61 | −7.14 | −6.73 | −7.55 | −8.20 | −7.30 | −6.89 | −6.74 | −8.12 |
Protein | Ligand | Interaction | |||
---|---|---|---|---|---|
Name | Chain: Residue | Name | Residue | Type | Distance [Å] |
CTD-SP1 (5I4T) | I:Lys227 | BVM | carboxylate | salt bridge | 1.90 |
J:Lys227 | carboxylate | attractive charge | 3.67 | ||
I:Pro224 | C-21 of betulin | carbon–hydrogen bond | 2.90 | ||
J:Lys227 | carboxylate | alkyl–alkyl | 2.11 | ||
L:Gly223 | carboxylate | alkyl–alkyl | 2.30 | ||
G:Lys158 | C-21 of betulin | alkyl–alkyl | 4.69 | ||
L:Pro224 | C-21 of betulin | alkyl–alkyl | 5.41 | ||
L:Lys158 | C-25 of betulin | alkyl–alkyl | 5.28 | ||
K:Lys158 | C-29 of betulin | alkyl–alkyl | 3.67 | ||
K:Lys158 | C-30 of betulin | alkyl–alkyl | 3.89 | ||
G:Lys158 | C-21 of betulin | alkyl–alkyl | 4.55 | ||
J:Lys158 | C-5′ of BVM | alkyl–alkyl | 3.71 | ||
J:Lys158 | C-6′ of BVM | alkyl–alkyl | 4.76 | ||
I:Lys227 | 14a | carboxylate | salt bridge | 1.99 | |
G:Lys158 | carboxylate | carbon–hydrogen bond | 2.98 | ||
K:Lys158 | carboxylate | carbon–hydrogen bond | 5.18 | ||
J:Lys227 | phosphonate | conventional hydrogen bond | 2.23 | ||
L:Lys158 | phosphonate | conventional hydrogen bond | 1.97 | ||
J:Lys227 | ethyl | carbon–hydrogen bond | 2.40 | ||
L:Lys158 | phosphonate | carbon–hydrogen bond | 2.19 | ||
J:Gly222 | ethyl | carbon–hydrogen bond | 3.59 | ||
I:Lys158 | C-25 of betulin | alkyl–alkyl | 5.23 | ||
K:Lys158 | C-24 of betulin | alkyl–alkyl | 4.94 | ||
I:Lys158 | C-7 of betulin | alkyl–alkyl | 4.38 | ||
H:Lys158 | ethyl | alkyl–alkyl | 5.23 | ||
J:Pro224 | ethyl | alkyl–alkyl | 4.08 | ||
H:Lys158 | ethyl | alkyl–alkyl | 3.69 |
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Chrobak, E.; Marciniec, K.; Dąbrowska, A.; Pęcak, P.; Bębenek, E.; Kadela-Tomanek, M.; Bak, A.; Jastrzębska, M.; Boryczka, S. New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study. Int. J. Mol. Sci. 2019, 20, 5209. https://doi.org/10.3390/ijms20205209
Chrobak E, Marciniec K, Dąbrowska A, Pęcak P, Bębenek E, Kadela-Tomanek M, Bak A, Jastrzębska M, Boryczka S. New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study. International Journal of Molecular Sciences. 2019; 20(20):5209. https://doi.org/10.3390/ijms20205209
Chicago/Turabian StyleChrobak, Elwira, Krzysztof Marciniec, Aleksandra Dąbrowska, Paweł Pęcak, Ewa Bębenek, Monika Kadela-Tomanek, Andrzej Bak, Maria Jastrzębska, and Stanisław Boryczka. 2019. "New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study" International Journal of Molecular Sciences 20, no. 20: 5209. https://doi.org/10.3390/ijms20205209