Pramod K. Sahu

Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N6-Substituted-(N)-Methanocarba-nucleosides as A3 Adenosine Receptor Antagonists and Partial Agonists

Truncated N6-substituted-(N)-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 hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N6-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f–4i did not differ significantly, with Ki values of 7.8–16.0 nM. N6-Methyl derivative 4b (Ki = 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; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.

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

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

Stereo- and regio-selective synthesis of 3′-C-substituted-(N)-methanocarba adenosines as potential anticancer agents

Stereo- and regio-selective synthesis of 3′-C-substituted-(N)-methanocarba adenosines 3a–c as potential anticancer agents was achieved by employing stereoselective cyclopropanation, stereoselective nucleophilic addition, regioselective isopropylidene cleavage and regioselective base condensation of cyclic sulfate as key steps.

Orally active, species-independent novel A 3 adenosine receptor antagonist protects against kidney injury in db/db mice

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A3AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD.Diabetic kidney disease: drug successfully targets key proteinA therapeutic treatment targeting a protein involved in the progression of diabetic kidney disease (DKD) shows promise in mouse trials. Between 30 and 40 per cent of diabetic patients suffer from DKD, a common cause to fatal end-stage kidney disease. Protein receptors, commonly expressed on cell surfaces throughout the body, play both positive and negative roles in diseases. The A3 adenosine receptor (A3AR) is highly expressed in diabetic kidney tissue, and is linked to disease progression. Hunjoo Ha at Ewha Womans University in Seoul, Republic of Korea, and co-workers demonstrated the positive effect of a novel drug in targeting A3AR in mice with DKD. A 12-week treatment of the drug prevented kidney injury, lowered oxidative stress and inflammation, and improved kidney function. It may prove an invaluable drug, particularly in combination with an existing DKD drug.

Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents

A series of acyclic selenopurine nucleosides 3a–f and 4a–g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e–g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d).

Stereoselective Synthesis of 4′‐Selenonucleosides via the Seleno‐Michael Reaction

5′‐Homo‐4′‐selenonucleosides, a class of next‐generation nucleosides, are synthesized from D‐ribose via a 4‐selenosugar intermediate. The key step in synthesizing this intermediate is a seleno‐Michael reaction. 5′‐Homo‐4′‐selenouridine and ‐adenosine are prepared using Pummerer‐type and Vorbrüggen condensation, respectively.