Adenine nucleoside, antiviral activity

De Clercq E, Descamps J, De Somer P, Holy A (1978) (S)-9-(2,3-Dihydroxypropyl)adenine an ahphatic nucleoside analog with broad-spectrum antiviral activity. Science 5 563-565 De Clercq E, Holy, A (2005) Acyclic nucleoside phosphonates a key class of antiviral drugs. Nature reviews 4 928-940... 

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

In recent years exceptional antiviral activity has been obtained with compounds which show structural analogy to the common purine nucleosides. In particular the substance acycloguanine (381) (78MI40909) and 9-(5-2,3-dihydroxypropyl)adenine (382) have high... 

The isothiazolo[4,5-d]pyrimidin-3-yl C-nucleoside analogs of adenine and guanosine, 559 and 560, respectively, were also synthesized (94JOC1912). C-Nucleosides 552,558,559, and 560 were tested for antiviral activity against HIV, HCMV, HSV, and rhinoviruses and found inactive (93JOC5181 94JOC1912). 

Oxetanocin oxetanocinA, 9-[(2/ ,3/ ,45)-3,4-bis-(hydroxymethyl)-2-oxetanyl]adenine. CioHijNgOj, Mr 251.24, needles (XH2O), mp. 197 °C, [a]g> -44.3° (pyridine), a nucleoside antibiotic from culture broths of Bacillus megaterium exhibiting antibacterial and potent antiviral activities. In the name O. A the A is in-... 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

In the realm of biological chemistry, in 2008, Lagisetty et al. [46] reported for the first time a simple method for the arylation at C-8 of adenine nucleosides. The motivation for this investigation was the observation that substitution at the C-8 position can influence the syn-anti conformational equilibrium around the glycosidic bond or produce structural factors that can influence enzymatic recognition. Purine derivatives are also of great importance in medicinal chemistry as they display a broad spectrum of antiviral and antimycobacterial activity. In this account iodo-, bromo-, and even chloro-aromatics were coupled with vinyl nucleosides. The reaction was catalyzed by the simple combination of Pd(OAc)2, (o-tolljP, and EtjN. The best conditions and some of the best representative results are shown in Figure 1.5. 

Both analogues can sm e to iUustrate an important problem frequently associated with design of new biologically active nucleoside analogues, namely, base selectivity. Thus, the antiviral effect of acyclovir (la), a guanine derivative, is unique. The corresponding adenine analogue (Ic), which is historically the first compound of this series, is much less effective. The thymine and cytosine derivatives lb. Id have virtually no antiviral activity. ... 

A series of novel acyclic nucleoside phosphonates (819) with various nucleobases in the oo-position and variously substituted in the p-position of alkylphosphonate chain, have been prepared by Hockowa et al. Several derivatives exhibited antiviral activity against HIV and vaccinia virus, HSV-1, HSV-2, VZV and CMV, although the parent unsubstituted derivatives were anti vitally inactive. Adenine as a nucleobase and the p-methyl group attached to the alkylphosphonate chain proved to be a prerequisite to afford pronounced antiviral activity. " ... 

Another nucleoside-derived mechanism-based enzyme inhibitor is Fluoronepla-nocin A [79]. This compound is of interest as a broad-spectrum antiviral drug which acts by irreversible inhibition of S-adenosylhomocystein hydrolase (SAH). In a first enzymatic reaction step the 3 -hydroxy group of the inhibitor is oxidized to the corresponding ketone (Scheme 4.34). This leads to depletion of the biochemical oxidizer nicotinamide adenine dinudeotide (NAD ). In the next step a nucleophilic residue of the enzyme undergoes Michael addition to the /i-fluoro a,/>-unsatu-rated ketone moiety. This is followed by fluoride elimination and thus the inhibitor stays covalently trapped in the active site and disables the enzyme permanently. 

Fludarabine phosphate, a fluorinated deamination-resistant nucleotide analog of the antiviral agent vidarabine (9-P-D-arabinofuranosyl-adenine), is active in CLL and low-grade lymphomas. After rapid extracellular dephosphorylation to the nucleoside fludarabine, it is rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. This antimetabolite inhibits DNA polymerase, DNA primase DNA ligase, and ribonucleotide reductase, and is incorporated into DNA and RNA. The triphosphate nucleotide is an effective chain terminator when incorporated into DNA, and the incorporation of fludarabine into RNA inhibits RNA function, RNA processing, and mRNA translation. 

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