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

Abstract

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.

Historical Perspectives in the Development of Antiviral Agents Against Poxviruses

“…In addition to the 5-substituted 2’-deoxyuridines, numerous other nucleoside analogs have been reported to inhibit VV at a sufficiently low IC 50 (<1 μg/ml) to be potentially useful from a therapeutic viewpoint [27]: i.e., IMP (inosine 5’-monophosphate) dehydrogenase inhibitors, such as EICAR (5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide) [17]; SAH (S-adenosylhomocysteine hydrolase) inhibitors, such as neplanocin A [37], 3-deazaneplanocin A [21], 9-( trans -2’, trans -3’-dihydroxycyclopent-4’-enyl)adenine (DHCeA) and -3-deazaadenine (c 3 DHCeA) [39], (1’ R ,2’ S ,3’ R )-9-(2’,3’-dihydroxycyclopentan-1’-yl)adenine (DHCaA) and -3-deazaadenine (c 3 DHCaA) [40], (±)-6’β-fluoroaristeromycin (F-C-Ado) [41], (±)-5’-noraristeromycin [42], (-)-5’-noraristeromycin [43], epi (-)-5’-noraristeromycin [44], (-)-3-deaza-5’-noraristeromycin [45], ( R )-6’- C -methylneplanocin A [46], 6’-homoneplanocin A [47], and 2-fluoroneplanocin A [48]; carbocyclic cyclopentenyl cytosine (Ce-Cyd) [49,50], a putative inhibitor of CTP synthetase; 8-methyladenosine [51], whose mechanism of action as an inhibitor of VV has never been clarified; the N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine S2242 [52], which is inhibitory to VV, as well as various herpesviruses (HSV, VZV, CMV), and whose antiviral activity, while depending on phosphorylation by deoxycytidine kinase (dCK) [53], was never fully elucidated; and adenine arabinoside, vidarabine (ara-A), the first antiviral drug to be approved for systemic use (for the treatment of VZV infections) [54], which is quite effective against VV replication in vitro [31] (the inhibition of VV replication by ara-A may be explained by the inhibitory effect of ara-ATP on viral DNA synthesis and/or a direct inhibitory effect of ara-A on SAH hydrolase, akin to that of all other adenosine analogs mentioned above (see supra ).…”

A Survey of Antiviral Drugs for Bioweapons

“…This plays a role in the 5′-cap formation and maturation of VV mRNA (Borchardt, 1980). Those that have marked activity against VV are C-c 3 Ado (De Clercq and Montgomery, 1983), neplanocin A and C (De Clercq, 1985), 3-deazoneplanocin A (De Clercq et al, 1989;Tseng et al, 1989), DHCeA and c 3 DHCeA (De Clercq et al, 1989;Hasobe et al, 1987) and its saturated derivatives, F-C-Ado (Cools et al, 1991), 5′-norasteromycin (Patil et al, 1992;Siddiqi et al, 1994;Siddiqi et al, 1995), R-6′-C-methylneplanocin A (Shuto et al, 1996), 6′-homoneplanocin A (Shuto et al, 1996), 2-fluoroneplanocin A (Obara et al, 1996), and 6′-iodo acetylenic Ado (Robins et al, 1998). These inhibitors all inhibit VV in cell culture at an IC 50 of less than 1 µg/ml with little to no cytotoxicity at the active concentrations.…”

New Neplanocin Analogues. 7. Synthesis and Antiviral Activity of 2-Halo Derivatives of Neplanocin A

“…The solvent was evaporated under vacuum and the residue was purified by flash chromatography (CHCl 3/MeOH/25% NH4OH, 200:10:0.5 followed by 200:40:2) to give 1b (41 mg, 40%) as a crystalline solid. An analytical sample was obtained by further purification by HPLC (eluent, 10% MeOH in H 2O) to give 2 (23 mg, 22%): mp >245 °C (dec); UV (H 2O) λmax 262 nm, 270 nm (shoulder); [R] 24 D -162 (c 0.10, H2O); 1…”