A series of phenanthroquinolizidine alkaloids 1–24 were prepared and first evaluated for their antiviral activity against tobacco mosaic virus (TMV). The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds 1, 2, 15 and 16 displayed significantly higher activity than (R)-antofine and commercial Ningnanmycin at the same test condition. The substituents on the phenanthrene moiety play an important role for maintaining high in vivo antiviral activity. The introduction of 6-hydroxyl, which is proposed to interact with TMV RNA, did increased anti-TMV activity. The 14aR-configuration was confirmed to be the preferred antiviral configuration for phenanthroquinolizidine alkaloids. Introduction of hydroxy group at 15-position of phenanthroquinolizidine alkaloids increased activity for S-configuration but decreased activity for R-configuration. Present study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.

Naturally occurring phenanthroindolizidine alkaloids (R)-antofine and phenanthroquinolizidine alkaloids (R)-cryptopleurine have been synthesized in high optical purity via proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde. Both enantiopure forms of proline are commercially available, and thus, in principle, both isomers of antofine and cryptopleurine can be accessed with the new method.

Papilistatin has been isolated recently and found to have good anticancer and antibacterial activity. Papilistatin is a unique phenanthrene-1,10-dicarboxylic acid. The first total synthesis of papilistatin is described here with radical cyclisation as the key step.

A series of 7-methoxycryptopleurine derivatives 2-23 were prepared and evaluated for their antiviral activity against tobacco mosaic virus (TMV) for the first time. The bioassay results showed that most of these compounds exhibited excellent in vivo anti-TMV activity, of which 7-methoxycryptopleurine salt derivatives 16, 19, and 23 displayed significantly higher activity than 7-methoxycryptopleurine (1) and commercial ribavirin and ningnanmycin. Salification, the most commonly employed method for modifying physical-chemical properties, did significantly increase antiviral activity, and different salt forms displayed different antiviral effect. This study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.