Synthesis of 3-deazaneplanocin A analogs and their antiviral activity against RNA-viruses

3-Deazaneplanosin A (DZNep, 2) analogs showed a broad spectrum of biological activity against some cancers and DNA/RNA viruses as a promising inhibitor of the S-adenosyl-L-homocysteine (SAH) hydrolase and the enhancer of zeste homolog 2 (EZH2). Recently, 3-halogenated DZNep analogs were reported as potent inhibitors against RNA viruses as an inhibitor of SAH hydrolase, but 6-halogenated DZNep and its analogs was not studied as an antiviral agent to date. Thus, N9-/N7-2,6-dihalo-DZNep and N7-6-amino/azido-DZNep analogs were prepared using Mitsunobu reaction of 3-deazapurine derivatives with chiral cyclopentene-1-ol derivatives (22a-b). With a modified procedure of a previous synthetic method, the chiral 22a and 22b were prepared in 50% overall yield from D-ribose. Additionally, 3-deazapurine analogs including 2,6-dibromo-3-deazapurine 30a, 2,6-dichloro-3-deazapurine 30b, 6-azido-3-deazapurine 36, N6-Bz-3-deazapurine 38a, and N6,N6-bisBz-3-deazapurine 38b were synthesized in 25–43% overall yields. Mitsunobu reaction of 30a-b with 22a afforded a mixture of N7-/N9-isomer in the ratio of 4:5 and 1:1, respectively. The reaction of 36 and 38a with 22a provided their corresponding only N7-isomer products, whereas N6,N6-bisBz-3-deazapurine (38b) gave single N9-isomer as a regioselective product. Among prepared DZNep analogs, novel N9-2,6-dibromo-3-deazaneplanocin (44a) exhibited the most potent activity (EC50 7.0 μM) against Flu A (H1N1) with CC50 >100 in vitro. Unexpectedly, N7-6-azido-3-deazaneplanocin (46) displayed EC50 22.5 μM, and 25.3 μM against Flu A (H1N1) and (H3N2) with CC50 >100, respectively. The other 3-DZNep analogs showed no significant antiviral potency against Flu A and B in vitro and against dengue virus-2 replicon. Currently, N9-2,6-dibromo-3-deazaneplanocin (44a) was found as a new heat compound for Flu A (H1N1).