Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

Khandazhinskaya, Anastasia L.; Fateev, Ilja V.; Konstantinova, Irina D.; Есипов, Р. С.; Polyakov, K.M.; Seley‐Radtke, Katherine L.; Kochetkov, Sergey N.; Matyugina, Elena S.

doi:10.3389/fchem.2022.867587

Cited by 3 publications

(5 citation statements)

References 32 publications

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“…This may be caused by the formation of a dead-end complex upon the binding of the heterocyclic base and an inorganic phosphate at the active site of the human enzyme. This was seen for various heterocyclic bases, including 7-deazahypoxanthine, in the case of E. coli PNP [ 10 ].…”

Section: Resultsmentioning

confidence: 93%

“…The first comprised pyrrole-containing fleximer bases 1–4, which were chosen due to the inhibitory activity exhibited by 7-deazahypoxanthine against E. coli PNP (Ki = 0.13 mM) [ 15 ]. Similarly, the acyclic 8-aza-7-deazapurine fleximers 13–16 were designed based on the structure of previously studied 5′-norcarbocyclic 8-aza-7-deazapurine fleximers, which showed weak inhibitory activity against E. coli PNP (Ki = 14–20 mM) [ 10 ] and acyclovir, which was able to inhibit h PNP (Ki = 90µM) [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that fleximer analogues of aza/deazapurine heterocyclic bases are substrates of E. coli purine nucleoside phosphorylase [ 9 ] while their 5′-norcarbocyclic derivatives are noncompetitive inhibitors of the same enzyme [ 10 ]. Both groups of compounds are members of the well-known fleximer class of nucleosides.…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP

et al. 2023

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The great interest in studying the structure of human purine nucleoside phosphorylase (hPNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, hPNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of E. coli PNP. Fleximers have great promise as they have exhibited significant biological activity against a number of viruses of pandemic concern. Herein, we describe the synthesis and inhibition studies of a series of new fleximer compounds against hPNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines 1–4, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine 2 was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand 2 is localized in the selected binding pocket Glu201, Asn243 and Phe200. The ability of the pyridine and pyrrole fragments to undergo rotation around the C–C bond allows for multiple binding modes in the active site of hPNP, which could provide several plausible bioactive conformations.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP

et al. 2023

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Section: Antimicrobial Studiesmentioning

confidence: 99%

“…In order to evaluate the antimicrobial effect of the fleximers, heterocyclic base analogues 1a and 1b, the new derivatives of 8-aza-7-deazahypoxanthine fleximers 2-9, and the previously reported 8-aza-7-deazapurine fleximer nucleoside analogues 10-22 [32,36,37] (Figure 1), were tested against a number of microorganisms. The antimicrobial activity of the compounds was studied as previously described [38] 19) and 1-(2 ,3 ,4trihydroxycyclopent-1 -yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole ( 9) inhibited the growth of M. smegmatis mc2 155 by 99% at concentrations (MIC 99 ) of 50 and 13 µg/mL, respectively.…”

Section: Antimicrobial Studiesmentioning

confidence: 99%

New Flexible Analogues of 8-Aza-7-deazapurine Nucleosides as Potential Antibacterial Agents

Khandazhinskaya,

Eletskaya,

Mironov

et al. 2023

IJMS

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A variety of ribo-, 2′-deoxyribo-, and 5′-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside (3) worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and M. tuberculosis. It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole (19) and 1-(2′,3′,4′-trihydroxycyclopent-1′-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole (9) were able to inhibit the growth of M. smegmatis mc2 155 by 99% at concentrations (MIC99) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol (10) and 1-(4′-hydroxy-2′-cyclopenten-1′-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole (6). At concentrations (MIC99) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of M. tuberculosis growth.

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Design of novel broad‐spectrum antiviral nucleoside analogues using natural bases ring‐opening strategy

Du,

Yang,

Zhao

et al. 2024

Drug Development Research

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The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA‐dependent RNA polymerase (RdRp) has emerged as a potential target for broad‐spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently‐used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the “ring‐opening” strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad‐spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high‐throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC50) value of 9.95 μM, which was superior to that of ribavirin (the positive control, IC50 = 11.43 μM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC50 of 30.82 μM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 μM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with “ring‐opening” bases and suggests the “ring‐opening” nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open‐loop bases to mimic Watson‐Crick base pairing better and improve antiviral activity.

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Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

Cited by 3 publications

References 32 publications

Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP

Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP

New Flexible Analogues of 8-Aza-7-deazapurine Nucleosides as Potential Antibacterial Agents

Design of novel broad‐spectrum antiviral nucleoside analogues using natural bases ring‐opening strategy

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