Stereoselective Synthesis of d‑5-Homo-4-selenoribose as a Versatile Intermediate for 4′-Selenonucleosides

Stereoselective synthesis of d-5-homo-4-selenoribose, serving as a versatile intermediate for the synthesis of 4′-selenonucleosides <b>12a</b>–<b>c</b>, was accomplished using Sharpless asymmetric epoxidation, regioselective cleavage of the α,β-epoxide, and stereoselective reduction of the ketone as the key steps

Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents

On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoacyclovir (<b>2a</b>) and selenoganciclovir (<b>2b</b>) were designed based on bioisoteric rationale and synthesized via the diselenide <b>7</b> as the key intermediate. Compound <b>2a</b> exhibited potent anti-HSV-1 and -2 activities while <b>2b</b> exerted moderate anti-HCMV activity, indicating that these nucleosides can serve as a novel template for the development of new antiviral agents

Asymmetric Synthesis of (−)-6′-β-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination

(−)-6′-β-Fluoro-aristeromycin (<b>2</b>), a potent inhibitor of <i>S</i>-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoaristeromycin (<b>2a</b>). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution

Stereoselective Synthesis of 4′-Selenonucleosides via Seleno-Michael Reaction as Potent Antiviral Agents

Based on the hypothesis that the bulky selenium atom, with 4p orbitals, can sterically hinder the approach of a cellular kinase to 5′-OH for phosphorylation, 4′-selenonucleosides with one-carbon homologation were designed and synthesized via a novel seleno-Michael reaction, with the stereoselectivity controlled by steric effects. 5′-Homo-4′-selenonucleosides (<i>n</i> = 2) demonstrated potent antiherpes simplex virus (HSV-1) activity, indicating that the bulky selenium atom might play a key role in preventing phosphorylation by cellular kinases, resulting in no antiviral activity

Polypharmacology of <i>N</i>⁶‑(3-Iodobenzyl)­adenosine-5′‑<i>N</i>‑methyluronamide (IB-MECA) and Related A₃ Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential

A₃ adenosine receptor (AR) ligands including A₃ AR agonist, <i>N</i>⁶-(3-iodobenzyl)­adenosine-5′-<i>N</i>-methyl­uronamide (<b>1a</b>, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, <b>1a</b> significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A₃ AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A₃ AR pathway may not be directly involved in the adiponectin promoting activity. In a target deconvolution study, their adiponectin-promoting activity was significantly correlated to their binding activity to both peroxisome proliferator activated receptor (PPAR) γ and PPARδ. They functioned as both PPARγ partial agonists and PPARδ antagonists. In the diabetic mouse model, <b>1a</b> and its structural analogues A₃ AR antagonists significantly decreased the serum levels of glucose and triglyceride, supporting their antidiabetic potential. These findings indicate that the polypharmacophore of these compounds may provide therapeutic insight into their multipotent efficacy against various human diseases

Fluorocyclopentenyl-cytosine with Broad Spectrum and Potent Antitumor Activity

On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from d-ribose. Among these, the cytosine derivative <b>5a</b> showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2′-deoxycytidine derivative <b>5b</b> did not show any antigrowth effects, indicating that 2′-hydroxyl group is essential for the biological activity

Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2‑Hexynyl‑<i>N</i>⁶‑Substituted‑(<i>N</i>)‑Methanocarba-nucleosides as A₃ Adenosine Receptor Antagonists and Partial Agonists

Truncated <i>N</i>⁶-substituted-(<i>N</i>)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4′-thioadenosines. Hydrophobic N⁶ and/or C2 substituents were tolerated in A₃AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA_2AAR affinity. A small hydrophobic alkyl (<b>4b</b> and <b>4c</b>) or <i>N</i>⁶-cycloalkyl group (<b>4d</b>) showed excellent binding affinity at the hA₃AR and was better than an unsubstituted free amino group (<b>4a</b>). A₃AR affinities of 3-halobenzylamine derivatives <b>4f</b>–<b>4i</b> did not differ significantly, with <i>K</i>_i values of 7.8–16.0 nM. <i>N</i>⁶-Methyl derivative <b>4b</b> (<i>K</i>_i = 4.9 nM) was a highly selective, low efficacy partial A₃AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A₃AR binding affinities were proportional to antifibrotic effects; <b>4b</b> was most potent (IC₅₀ = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Truncated <i>N</i>⁶-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A_2A and A₃ adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA_2AAR, but hydrophobic C8 substitution abolished binding at the hA_2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA₃AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA_2AAR agonists. C2 substitution probed geometrically through hA_2AAR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound <b>4g</b> was the most potent ligand acting dually as hA_2AAR agonist and hA₃AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases