New Neplanocin Analogues. IV. 2-Fluoroneplanocin A: An Adenosine Deaminase-Resistant Equivalent of Neplanocin A.

Shuto, Satoshi; Obara, Takumi; Itoh, Hiromichi; Kosugi, Yoshinori; Saito, Yasuyoshi; Toriya, Minoru; Yaginuma, Satoshi; Shigeta, Shirô; Matsuda, Akira

doi:10.1248/cpb.42.1688

Cited by 13 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sugar ring conformation has also been reported to play an important role in ADA recognition; the enzyme has been reported to deaminate nucleosides biased toward the north conformation up to 65-fold faster than those biased toward the south conformation (43)(44)(45)(46). Additionally, 2-fluoro-2=-deoxyadenosine (FdA) analogs are somewhat resistant to ADA-mediated catabolism due to the electron withdrawing properties of the 2-fluoro group (47,48), and we have previously reported that EFdA is poorly deaminated by ADA because of the 2-fluoro group (21). However, the effects of specific 4= substitutions on sugar ring conformation and how these substitutions would affect the recognition of the compounds by HIV RT and ADA have not been determined.…”

mentioning

confidence: 99%

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Kirby

Michailidis

Fetterly

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

i Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) is a highly effective NRTI; however, the reasons for the potent antiviral activity of EFdA are not well understood. Here, we use a combination of structural, computational, and biochemical approaches to examine how substitutions in the sugar or adenine rings affect the incorporation of dA-based NRTIs like EFdA into DNA by HIV RT and their susceptibility to deamination by adenosine deaminase (ADA). Nuclear magnetic resonance (NMR) spectroscopy studies of 4=-substituted NRTIs show that ethynyl or cyano groups stabilize the sugar ring in the C-2=-exo/C-3=-endo (north) conformation. Steady-state kinetic analysis of the incorporation of 4=-substituted NRTIs by RT reveals a correlation between the north conformation of the NRTI sugar ring and efficiency of incorporation into the nascent DNA strand. Structural analysis and the kinetics of deamination by ADA demonstrate that 4=-ethynyl and cyano substitutions decrease the susceptibility of adenosinebased compounds to ADA through steric interactions at the active site. However, the major determinant for decreased susceptibility to ADA is the 2-halo substitution, which alters the pK a of N1 on the adenine base. These results provide insight into how NRTI structural attributes affect their antiviral activities through their interactions with the RT and ADA active sites. There are 10 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) that are currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infections (1-5). Several more nucleoside analog drugs are approved or being studied for the treatment of viruses, such as herpes simplex virus (HSV), hepatitis C virus (HCV), and hepatitis B virus (HBV), or as anticancer agents (6-10). NRTIs are among the most effective anti-HIV drugs. All approved anti-HIV NRTIs lack a 3=-hydroxyl moiety and, thus, act as chain terminators following their incorporation by the viral reverse transcriptase (RT) into the nascent DNA chain. However, the absence of a 3=-OH, while essential for the inhibition of DNA synthesis, also imparts detrimental properties to these inhibitors, including reduced intracellular phosphorylation to the active triphosphate form and reduced RT binding affinity (11). Prolonged exposure to NRTI-based treatments causes mitochondrial toxicity (12-14) and leads to the development of NRTI resistance mutations (15-18), giving rise to complications in the treatment of HIV-infected patients.Ideally, an NRTI should have a strong binding affinity for the RT target, a high barrier for the development of resistance, and low toxicity. We have reported that a series of 4=-substituted nucleosides in which the 3=-OH is retained has exceptional inhibitory activity against HIV-1 RT (19). Among these compounds, 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) is a highly active RT inhibitor that prevents translocation of the nucleic acid from the n...

show abstract

mentioning

confidence: 99%

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Kirby

Michailidis

Fetterly

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Jacobson and coworkers [30] have synthesized various cyclopropyl-fused 2 0 -deoxyneplanocin A analogues (56)(57)(58), and investigated their binding affinity for adenosine receptors (Scheme 21.11). The key carbasugar 54 was synthesized from the known cyclopentenone derivative 15 [31].…”

Section: Modifications On Neplanocin a And Aristeromycinmentioning

confidence: 99%

“…Matsuda and coworkers [56,57] have reported the antiviral activity of various 2-halo derivatives of neplanocin A (Figure 21.5).…”

Section: Base Modificationmentioning

confidence: 99%

Syntheses and Biological Activity of Neplanocin and Analogues

Tosh

Kim

Pal

et al. 2008

Modified Nucleosides

View full text Add to dashboard Cite

IntroductionNeplanocin A (1) [1] is a carbocyclic nucleoside which is isolated from Ampullariella regularis and possesses excellent chemical and metabolic stability of the glycosidic bond ( Figure 21.1). Neplanocin A also exhibits potent biological activity such as antiviral and antitumor activities, which result from the inhibition of S-adenosyl-SAH hydrolase catalyzes the interconversion of SAH into adenosine and L-homocysteine [4], and inhibition of this enzyme leads to an accumulation of SAH and a negative inhibition of cellular S-adenosyl-L-methionine (SAM)-dependent methyltransferase ( Figure 21.2). As SAM-dependent methyltransferase is responsible for formation of the 5 0 -terminal methylated N 7 -methylguanosine cap of the mRNA in most animal-infecting viruses, SAH hydrolase is essential for viral replication [4, 5]. Thus, the inhibition of SAH hydrolase can exhibit a broad spectrum of antiviral activity [6].Neplanocin A is one of the most potent inhibitors of SAH hydrolase, and shows a strong antiviral activity against various RNA and DNA viruses. Neplanocin A inhibits SAH hydrolase by virtue of a cofactor-depleting mechanism [5,7,8], and is oxidized to its 3 0 -keto form by the enzyme-bound cofactor NAD þ , which is tightly bound to the reduced cofactor NADH, resulting in the depletion of NAD þ . However, despite its potent enzyme inhibitory activity, neplanocin A could not be developed as a clinically useful antiviral agent because it proved to be too toxic to the host cells. This toxicity was derived from the triphosphorylation of the 5 0 -hydroxyl group of neplanocin A by cellular kinases (including adenosine kinase [9, 10]), with the resultant triphosphate being incorporated into RNA and causing the inhibition of RNA synthesis [10].Aristeromycin (2) [11] is another natural product isolated from Streptomyces citricolor, and has a similar carbocyclic skeleton as neplanocin A, but is devoid of the C4 0 ¼C6 0 double bond. Like neplanocin A, aristeromycin also shows potent inhibitory activity against SAH hydrolase, but again also proved to be cytotoxic and could not be developed as an antiviral agent. The cellular toxicity of aristeromycin was Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

show abstract

“…It has been recognized that the detrimental toxicity of NPA could be derived, for the most part, from phosphorylation of the primary hydroxyl group at its 6‘-position (the 6‘-position of NPA corresponds to the 5‘-position of Ado) by Ado kinase and subsequent metabolism by cellular enzymes . NPA is also rapidly deaminated by Ado deaminase to a chemotherapeutically inactive inosine congener,9a which may account for the reduced therapeutic potency of NPA, especially in vivo . On the basis of these observations, chemical modifications of NPA have been extensively studied to develop efficient antiviral agents. , …”

Section: Introductionmentioning

confidence: 99%

New Neplanocin Analogues. 6. Synthesis and Potent Antiviral Activity of 6‘-Homoneplanocin A

et al. 1996

Self Cite

View full text Add to dashboard Cite

The design, synthesis, and antiviral activities of 6'-homoneplanocin A (HNPA, 3) and its congeners having nucleobases other than adenine, such as 3-deazaadenine (4), guanine (5), thymine (6), and cytosine (7), were described. Starting from the known cyclopentenone derivative 8, the optically active (mesyloxy)cyclopentene derivative 15 was prepared, which was condensed with nucleobases then deprotected to give target compounds 3-7. Of these compounds, HNPA showed an antiviral activity spectrum that was comparable to, and an antiviral specificity that was higher than, that of neplanocin A. HNPA proved particularly active against human cytomegalovirus, vaccinia virus, parainfluenza virus, vesicular stomatitis virus, and arenaviruses, which is compatible with an antiviral action targeted at S-adenosylhomocysteine hydrolase. HNPA appears to be a promising candidate drug for the treatment of these viruses.

show abstract

New Neplanocin Analogues. IV. 2-Fluoroneplanocin A: An Adenosine Deaminase-Resistant Equivalent of Neplanocin A.

Cited by 13 publications

References 0 publications

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Effects of Substitutions at the 4′ and 2 Positions on the Bioactivity of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Syntheses and Biological Activity of Neplanocin and Analogues

New Neplanocin Analogues. 6. Synthesis and Potent Antiviral Activity of 6‘-Homoneplanocin A

Contact Info

Product

Resources

About