New neplanocin analogs. 1. Synthesis of 6'-modified neplanocin A derivatives as broad-spectrum antiviral agents

Abstract

Novel neplanocin A analogues modified at the 6'-position, i.e., 6'-deoxy analogues (2, 3, 6, 9, 20), 6'-O-methylneplanocin A (15), and 6'-C-methylneplanocin A's (22a and 22b) have been synthesized and evaluated for their antiviral activity in a wide variety of DNA and RNA virus systems. These compounds showed an activity spectrum that conforms to that of S-adenosylhomocysteine hydrolase inhibitors. They were particularly active against pox- (vaccinia), paramyxo-(parainfluenza, measles, respiratory syncytial), arena- (Junin, Tacaribe), rhabdo- (vesicular stomatitis), reo-, and cytomegalovirus. In order of (increasing) antiviral activity, the compounds ranked as follows: 3 less than 15 approximately 20 less than 6 less than 9 approximately 2 less than 22a. Of the two diastereomeric forms of 22, only 22a was active; 22a surpassed neplanocin A both in antiviral potency and selectivity. Compound 22a appears to be a promising candidate drug for the treatment of pox-, paramyxo-, arena-, rhabdo-, reo-, and cytomegalovirus infections.

Antiviral activities of ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, and 6'-(R)-6'-C-methylneplanocin A against several ortho- and paramyxoviruses

“…The sources of the three compounds used in this study were TJ13025, Toyo Jozo Research Center, Ohito, Shizuoka, Japan (16).…”

“…Inhalation of aerosolized ribavirin by infants with RSV pneumonia or college students with influenza A leads to an improvement of the clinical symptoms in these patients (7,19,20). The mechanism of action of ribavirin and its metabolism by cells have been investigated (5,6,17,18,21); the main targets for the antiviral action of ribavirin and its phosphorylated form appear to be IMP dehydrogenase, viral mRNA cap formation, and viral RNA transcriptase or polymerase.Recently, we have reported two novel nucleoside analogs, 5 -ethynyl -1-, -D -ribofuranosylimidazole -4 -carboxamide (EICAR) and 6'-(R)-6'-C-methylneplanocin A (TJ13025), as broad-spectrum antiviral agents active against a wide variety of pox-, toga-, reo-, myxo-, rhabdo-, and arenaviruses in vitro (3,16). In this study, we have evaluated the inhibitory effects of EICAR and TJ13025 in comparison with those of ribavirin on the in vitro replication of several ortho-and paramyxoviruses.…”

“…Recently, we have reported two novel nucleoside analogs, 5 -ethynyl -1-, -D -ribofuranosylimidazole -4 -carboxamide (EICAR) and 6'-(R)-6'-C-methylneplanocin A (TJ13025), as broad-spectrum antiviral agents active against a wide variety of pox-, toga-, reo-, myxo-, rhabdo-, and arenaviruses in vitro (3,16). In this study, we have evaluated the inhibitory effects of EICAR and TJ13025 in comparison with those of ribavirin on the in vitro replication of several ortho-and paramyxoviruses.…”

Novel Carbocyclic Nucleosides Containing a Cyclobutyl Ring: Adenosine Analogues.

“…With regard to VV, the moderate activities of compounds 14 and 15 against this virus are similar to that of IIIc (like 14 and 15 a 6-amino-8-azapurine derivative), which shows that an extra methyl group on the carbon bearing the hydroxyl of these compounds does not greatly alter their anti-VV activity, which remains of a magnitude similar to that of ribavirin and well below that of brivudin. With regard to RSV, the marked activity of the 6-aminopurine IIIb (about 15-fold less than those of neplanocin A and 6Ј-C-methylneplanocin A, 14) but of the same magnitude as that of ribavirin and more than 130-fold more active than brivudin) is retained by the type V analogue 9 but not by the type VI analogue 10. Curiously, anti-RSV activity of the same magnitude as that of IIIb is displayed by the type VI hypoxanthine derivative 8, whereas the corresponding type V analogue 7 is inactive.…”

“…13) In addition, it has been reported that a 6Ј-C-methylneplanocin A (IVa) is more potent and/or selective than neplanocin A (IVb) against cytomegalovirus, vaccinia virus, parainfluenza virus, measles virus, respiratory syncytial virus, Junin virus, Tacaribe virus, vesicular stomatitis virus and reovirus. 14) This fact suggested to us to extend our research to compounds in which the cyclobutane ring bears a 1-hydroxyethyl group instead of the hydroxymethyl group of compounds III.…”