Abstract
On the basis of the previously reported polypharmacological profile of truncated d-1′-homologated adenosine derivatives [J. Med. Chem. 2020, 63, 16012.], the l-nucleoside analogues were synthesized using computer-aided design and evaluated for biological activity. The target molecules were synthesized from d-ribose via the key intramolecular cyclization of the monotosylate and Mitsunobu condensation. The peroxisome proliferator-activated receptor (PPAR) binding activities of l-nucleoside analogue 2d (Ki = 4.3 μM for PPARγ and 1.0 μM for PPARδ) were significantly improved in comparison with those of the d-nucleoside compound 1 (11.9 and 2.7 μM, respectively). In addition, the l-nucleosides showed more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues.
Keywords: l-Nucleoside, truncated 1′-homologated adenosine derivative, PPAR modulators, adiponectin
Modified nucleosides1 originating from natural DNA and RNA building blocks have been used to treat cancer or viral infections for the past 60 years. This involves several processes such as cellular and viral metabolism, DNA/RNA synthesis, and enzyme regulation. These modified nucleosides exert their cytotoxic effects by imitating endogenous nucleosides and act as antimetabolites. Moreover, at least some modified nucleosides may bind to several physiological targets and exhibit polypharmacological activities.2a These “off-target” activities could be used to develop new therapeutic agents2b because many drug–target combinations exist.
Nucleoside analogues are chemically modified compounds that mimic natural nucleosides and thus can interact with cellular enzymes and interfere with crucial processes in nucleic acid metabolism. Because the potency of modified nucleosides depends on their ability to imitate their physiological counterparts, it had been believed that d analogues, which have the same stereochemistry as natural nucleosides, could effectively be developed as therapeutic agents on the basis of the believed enzyme stereospecificity2c in organisms. At the beginning of the 1990s, this assumption was changed, and l-nucleoside enantiomers (mirror images of the natural d-nucleosides) appeared as a new breakthrough2d in therapeutic agents (Figure 1). Since Smejkal and Sorm reported the first synthesis of l-nucleoside in 1964,2e the discovery of racemic (±)-BCH-189,2f which has antiviral activity, aroused interest in the biology of l-nucleosides. The l enantiomer of (±)-BCH-189 showed greater potency against both HBV and HIV-1 (EC50 = 0.01 and 0.002 μM, respectively) compared with its d counterpart (EC50 = 0.5 and 0.2 μM, respectively). This l-nucleoside, known as lamivudine (3TC), became the first approved l-nucleoside for the treatment of HIV and HBV. Since then, many l-nucleoside analogues, such as clevudine, telbivudine, elvucitabine, and levovirin, have been approved and are currently in the market, and many others are currently in preclinical trials, such as 5FTRX2g for acute myeloid leukemia treatment. The potential advantages in the design and synthesis of l-nucleosides include lower toxicity, greater metabolic stability, and in some cases improved biological activity.
Figure 1.
(a) Natural d-nucleosides and (b) l-nucleosides that are currently approved or undergoing preclinical studies.
We recently reported that truncated d-1′-homologated adenosine derivatives3a showed polypharmacological profiles such as modulation of peroxisome proliferator-activated receptors (PPARs) and adiponectin production. PPARs are known to control metabolic homeostasis, and their modulating ligands have been developed for the treatment of metabolic disease.3a,3b However, safety issues such as hepatotoxicity and adverse cardiovascular effects were raised by the use of highly specific PPARγ or PPARδ agonists. Thus, with the anticipation that these serious side effects may be reduced by balanced PPAR activation, dual- or pan-PPAR modulators have been developed instead.3c In our previous study, the novel d-1′-homologated adenosine derivatives functioning as dual PPARγ partial agonists and PPARδ antagonists or PPARγ/δ dual modulators significantly increased adiponectin production for a period of adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs) and provided therapeutic potential against metabolic diseases and hypoadiponectinemia-associated cancer.
On the basis of that study, l-nucleoside enantiomers were designed through computer-aided drug design (CADD) and synthesized in order to demonstrate their improved PPAR- and adiponectin-secretion-modulating activities (Figure 2).
Figure 2.
Computer-aided drug design of l-truncated 1′-homologated adenosine derivatives.
In the computational docking study carried out with the use of Flare software,4 the docking score for l-nucleoside 2d against the PPARγ ligand-binding domain (LBD) (LF ΔG = −9.693) was similar to that for d-nucleoside 1 (LF ΔG = −9.648). However, in a docking study against the PPARδ LBD, 2d (LF ΔG = −9.717) showed slightly improved binding affinity compared with 1 (LF ΔG = −9.572). On the basis of this computational analysis, we report on the design and synthesis of l-1′-homologated adenosine derivatives 2a–h and their PPAR- and adiponectin-secretion-modulating activities.
In order to synthesize the final nucleoside analogues, glycosyl donor 9 was synthesized in a few steps and then condensed with a purine base. As shown in Scheme 1, d-ribose was protected to obtain 2,3-acetonide 5 by the use of acetone and a catalytic amount of sulfuric acid. The primary hydroxyl group of 5 was protected with a trityl (Tr) group to form intermediate 6, which was reduced with NaBH4 to afford diol 7. Regioselective tosylation of the primary alcohol of 7 was followed by tandem intramolecular cyclization to produce 4-oxo sugar 8.5 The Tr group of 8 was removed by treatment with diethylaluminum chloride6 to produce the key glycosyl donor 9. The process of synthesizing the base-condensed intermediates was carried out by treatment of 9 with 2,6-dichloropurine and 6-chloropurine under Mitsunobu conditions.7 The final truncated 1′-homologated adenosine derivatives 2a–h were obtained by treatment of 10 or 11 with 3-halobenzylamines followed by acetonide deprotection.
Scheme 1. Synthesis of l-Truncated Homologated 4′-Oxoadenosine Derivatives 2a–h.
Reagents and conditions: (a) cat. H2SO4, acetone, rt, 3 h; (b) trityl chloride, DMAP, pyridine/CH2Cl2 (1:1), 50 °C, 5 h; (c) NaBH4, EtOH, rt, 2 h; (d) TsCl, DMAP, pyridine, CH2Cl2, 50 °C, 5 h; (e) Et2AlCl, CH2Cl2, −40 °C, 2 h; (f) 2,6-dichloropurine or 6-chloropurine, PPh3, DIAD, THF, 60 °C, 24 h; (g) 3-halobenzylamines, Et3N, THF, rt, 20 h; (h) 1 N HCl, MeOH, 60 °C, 28 h.
The docking modes and docking scores against the PPARs were calculated in order to shed some light on the different biological activities of d-nucleoside 1 and l-nucleoside 2d against PPARs (Figure 3 and Table 1). In docking simulations of 1 and 2d against the PPARγ LDB (PDB ID 5YCP),8 two hydroxyl groups in 1 and 2d similarly form three hydrogen bonds with Tyr473 and Ser289. In both 1 and 2d, N7 forms a sulfur–lone pair interaction9 with Met364. However, l-nucleoside 2d has one additional hydrogen bond between the oxolane oxygen atom and the His449 residue at a distance of 2.7 Å (Figure 3a). This additional binding could explain the improved binding affinity of 2d. In docking simulations of 1 and 2d against the PPARδ LDB (PDB ID 5U46),10 the sugar moieties of 1 and 2d point in opposite directions, and 2d has additional hydrogen bond between the hydroxyl group and the Glu259 residue at a distance of 1.8 Å. The new hydrogen bond could be the reason for the improved binding affinity of 2d (Figure 3b).
Figure 3.
Superimposed structures of d-nucleoside (1) (green) and l-nucleoside (2) (purple) against (a) PPARγ and (b) PPARδ. All molecular graphics were generated using Flare software.
Table 1. Molecular Docking Scores for 1 and 2d against PPARγ/δ.
| compound | docking score (LF ΔG) for PPARγ | docking score (LF ΔG) for PPARδ |
|---|---|---|
| 1 | –9.648 | –9.572 |
| 2d | –9.693 | –9.717 |
As previously mentioned, compound 1 has been described as a PPARγ/δ dual modulator3 promoting adiponectin production during adipogenesis of hBM-MSCs. Therefore, we investigated whether compounds 2a–h exhibit an improved pharmacological profile compared with compound 1 using a time-resolved fluorescence resonance energy transfer (TR-FRET)-based PPAR competitive binding assay (Table 2). This assay uses a fluorescent PPAR ligand and a terbium-labeled PPAR LBD, where ligand binding induces energy transfer from terbium to the fluorophore of the ligand to increase the fluorescence emission.3 Competitive binding can be measured as the ability of a test compound to displace the fluorescent ligand from the PPAR LBD, leading to changes in the fluorescence intensity. The TR-FRET-based competitive binding assays for three PPAR subtypes showed the selective replacement of the fluorescent ligand by the corresponding known ligands (Table 2). The PPARα competitive binding assay showed that compounds 2a–h exhibited PPARα binding affinities lower than 20% at 10 μM, which is similar to that of compound 1 (Table 2).
Table 2. Receptor Binding Profiles of l-1′-Homologated Adenosine Derivatives 2a–h.
|
Ki (μM) or % replacementa |
|||||
|---|---|---|---|---|---|
| Cpd | X | Y | PPARα | PPARγ | PPARδ |
| 1 | – | – | 3.9% | 11.9 μM | 4.3 μM |
| 2a | Cl | F | 14.5% | 6.3% | 29.5% |
| 2b | Cl | Cl | 19.1% | 10.7% | 46.3% |
| 2c | Cl | Br | 8.7% | 25.5% | 3.4 μM |
| 2d | Cl | I | 17.2% | 2.7 μM | 1.0 μM |
| 2e | H | F | 7.6% | 11.5% | 8.0% |
| 2f | H | Cl | 3.1% | 5.9% | 21.5% |
| 2g | H | Br | 3.8% | 12.5% | 1.2% |
| 2h | H | I | 13.2% | 3.9% | 16.3% |
| 12 | – | – | 0.01 μM | ND | ND |
| 13 | – | – | ND | 0.07 μM | ND |
| 14 | – | – | ND | ND | 0.08 μM |
Binding affinities to PPARs were determined using TR-FRET-based PPAR competitive binding assays. Ki, inhibition constant; ND, not determined. GW7647, GW1929, and GW501516 were used as positive controls for the PPARα, PPARγ, and PPARδ competitive binding assays, respectively. Ki values were determined using the Cheng–Prusoff equation.3 In cases showing 50% or more binding affinity at a concentration of 10 μM, the Ki values were calculated; otherwise, the % replacement values at 10 μM are provided.
In the PPARγ binding assay, compounds 2c and 2d replaced the labeled PPARγ competitor by over 20%; compound 2d, the l-nucleoside analogue of compound 1, bound to PPARγ by over 50% at a concentration of 10 μM (Table 2). For PPARδ, compounds 2a–d displayed significant binding affinity, whereas compounds 2e–h had no effect (Table 2). Notably, the 2-chlorine substituent in compounds 2a–d was a key determinant of dual receptor-binding activity against both PPARγ and PPARδ. When the inhibition constants (Ki) of l-nucleoside analogue 2d against PPARγ and PPARδ were determined, 2d showed significantly improved binding affinity (2.7 μM for PPARγ and 1.0 μM for PPARδ) compared with 1 (11.9 and 4.3 μM, respectively) (Table 2).
The PPAR competitive binding assays showed that compound 2d was a PPARγ/δ dual modulator. Compound 1 also functioned as a PPARγ partial agonist and a PPARδ antagonist.3 We then investigated the pharmacological mechanisms of 2d on PPARγ and PPARδ binding (Figure 4). First, in order to evaluate the functional influence of 2d on PPARγ activation, the TR-FRET-based PPARγ coactivator assay was performed using fluorescein-labeled peptides from the following coactivators: mediator of RNA polymerase II transcription subunit 1 (TRAP220), PPARγ coactivator 1-alpha (PGC-1α), steroid receptor coactivators 1–3 (SRC-1, SRC-2, and SRC-3), D22 (sequence from multiple coactivators including PGC-1α and RIP140), and nuclear receptor-interacting protein 1 (RIP140).3 The results of the PPARγ coactivator assays showed a strong influence of compound 2d on the recruitment of the coactivator peptides TRAP220 and PGC-1α. The effect on TRAP220 was over 50%, whereas 2d had little effect on the recruitment of the peptides SRC-1, SRC-2, SRC-3, D22, and RIP140 (Figure 4A). In contrast, compound 2d did not change the levels of interaction between the PPARγ LBD and the fluorescein-labeled peptide from nuclear receptor corepressor 1 (NCoR1) (Figure 4B).
Figure 4.
Effects on PPAR coactivation of 2d. (A) Results of the TR-FRET-based PPARγ coactivator assay performed using coactivators TRAP220, PGC-1α, SRC-1, SRC-2, SRC-3, D22, and RIP140. (B) Results of the TR-FRET-based PPARγ corepressor assay performed using corepressor NCoR1 peptide. The PPARγ agonist GW1929 (GW19′) and pioglitazone (Pio) were used as controls for coactivation assays, while the PPARγ antagonist GW9662 (GW96′) was used as a control for the corepression assay. (C, D) Results of TR-FRET-based PPARδ corepressor analyses conducted using (C) corepressor peptide NCoR2 and (D) coactivator peptide C33. The PPARδ agonists GW501516 (GW50′) and GSK0660 (GSK0′) were used as controls. (E) Results of concentration-effect analysis on PPARδ corepression for compounds 1 and 2d. Bar or symbol heights and error bars represent means and standard deviations, respectively, from three independent measurements. P values were determined by the two-tailed Mann–Whitney test, and statistical significances are marked by the following criteria: *, P < 0.05; **, P < 0.01.
Notably, GW1929 and pioglitazone, both of which are full PPARγ agonists, increased the recruitment of all tested coactivators significantly, but to different extents. These results confirmed that 2d acted as a partial agonist of PPARγ, as did compound 1.
Next, we investigated the functional effect of 2d against PPARδ. In the PPARδ coactivator/corepressor assays, the PPARδ antagonist recruited the peptide sequence from nuclear receptor corepressor 2 (NCoR2), and the PPARδ agonist recruited the coactivator peptide C33 (sequence from multiple coactivators including TRAP220 and RIP140).3 The results of these studies showed that 2d acts as an antagonist of PPARδ because this compound significantly recruited corepressor NCoR2 to the PPARδ LBD and did not recruit coactivator C33 peptide, as did compound 1 (Figure 4C,D). The concentration-effect analysis indicated that 2d (EC50 = 9.3 μM) showed comparable or greater potency for PPARδ antagonism relative to compound 1 (18.8 μM) (Figure 4E).
The next step of our investigation was the evaluation of the adiponectin-secretion-promoting activity of compounds 2a–h. hBM-MSCs were differentiated in adipogenesis-inducing medium containing insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IDX conditions) for 5 days with the test compounds. In this system, the antidiabetic drugs pioglitazone and glibenclamide increased adiponectin production by 7.8- and 6.2-fold, respectively, relative to IDX conditions at 10 μM (Figure 5A). Although their efficacy of adiponectin production was not as potent as that of the positive-control drugs, compounds 2b, 2c, 2d, 2g, and 2h showed significant adiponectin-secretion-promoting activity during adipogenesis of hBM-MSCs (Figure 5A). The level of adiponectin production was increased by 5.7-fold relative to IDX conditions by treatment with 2d (30 μM). Notably, Pearson correlation analysis showed that the levels of adiponectin production (Figure 5A) and the levels of PPARγ or PPARδ binding (Table 2) of compounds 2a–h were significantly correlated (PPARγ R2 = 0.60, P < 0.05; PPARδ R2 = 0.73, P < 0.01), indicating that PPARγ/δ binding of the compounds affects adiponectin production. The concentration-effect analysis performed for adiponectin production showed half-maximal effective concentrations (EC50) equal to 47.3 for 1 and 21.9 μM for 2d (Figure 5B). Phenotypic analysis by Oil Red O staining after adipogenesis revealed that 2d also increased the number and size of lipid droplets during adipogenesis of hBM-MSCs (Figure 5C–F).
Figure 5.
Effects on adiponectin production during adipogenesis of 2a–h. (A) hBM-MSCs were differentiated for 5 days under IDX conditions with or without compounds, and the adiponectin levels in the supernatant were measured through an enzyme-linked immunosorbent assay (ELISA). The PPARγ agonists pioglitazone (Pio) and glibenclamide (Gli) were used as positive controls. (B) Results of concentration-effect analysis for adiponectin production. Bar or symbol heights and error bars represent means and standard deviations, respectively, from three independent measurements. P values were determined by the two-tailed Mann–Whitney test, and statistical significances were marked by the following criteria: *, P < 0.05; **, P < 0.01. (C–F) Results of phenotypic analysis of adipocyte differentiation using Oil Red O staining for (C) the vehicle control, (D) pioglitazone, (E) 1, and (F) 2d under IDX conditions after 5 days of adipogenesis. Scale bars represent 100 μm.
In summary, 2d and other l-nucleosides of truncated 1′-homologated adenosine derivatives in the series have adiponectin-secretion-promoting activity and function as dual PPARγ/δ modulators. Importantly, l-nucleoside analogue 2d exhibited improved pharmacological activity compared with d-nucleoside compound 1.
In this study, a series of l-nucleosides of truncated 1′-homologated adenosine derivatives were synthesized using computer-aided design. Because of the different configurations, the binding mode of l-nucleoside 2d against PPARs was improved in comparison with that of d-nucleoside 1. In activity assays, the l-nucleoside analogues showed improved dual activity as PPARγ partial agonists and PPARδ antagonists compared with the d-nucleoside analogues. Moreover, the l-nucleoside analogues exhibited more potent adiponectin-secretion-promoting activity than the d-nucleoside analogues, which is essential for treating hypoadiponectinemia-related diseases. Hypoadiponectinemia is a major phenotype in various metabolic diseases, such as diabetes, obesity, atherosclerosis, and some cancers. Further chemical modification of l-nucleosides is expected to lead to the discovery of potent therapeutic agents against cancer or metabolic diseases.
Acknowledgments
This study was financially supported by the National Research Foundation (NRF) (Grants NRF-2019R1F1A1063905, NRF-2019R1A2C2085749, and NRF-2022R1I1A3056585), the Ministry of Health & Welfare (HI20C0079), and Chonnam National University (Grant 2021-2440) of Korea. The authors are grateful to the Center for Research Facilities at Chonnam National University and the Korea Basic Science Institute for their assistance in the analysis of the organic structures (FT-NMR, HRMS).
Glossary
Abbreviations
- PPAR
peroxisome proliferator-activated receptor
- hBM-MSCs
human bone marrow mesenchymal stem cells
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00159.
Experimental procedures and product characterization, biology (PPARs, adiponectin), and copies of 1H and 13C NMR spectra (PDF)
Author Contributions
# M. Nguyen and S. An contributed equally to this work.
The authors declare no competing financial interest.
Special Issue
Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.
Supplementary Material
References
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