phenanthroquinolizidine and tylophorine

The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC₅₀) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC₅₀ values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection.

Topics: Alkaloids; Animals; Antiviral Agents; Apocynaceae; Chlorocebus aethiops; Coronavirus Infections; Cytopathogenic Effect, Viral; Dose-Response Relationship, Drug; Gastroenteritis, Transmissible, of Swine; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Rats; Rats, Sprague-Dawley; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Structure-Activity Relationship; Swine; Transmissible gastroenteritis virus; Tylophora; Vero Cells

The total synthesis of alkaloids phenanthroindolizidine 1a, tylophorine 1b, and phenanthroquinolizidine 1c, has been achieved in 46%, 49%, and 42% overall yield, respectively, starting from the corresponding phenanthrene-9-carboxaldehyde. Compound exhibited potent inhibition activity in three human cancer cell lines, with IC(50) values ranging from 104 to 130 nM. The structure-activity relations of these alkaloids and some of their synthetic intermediates against the three cell lines were also described.

Topics: Alkaloids; Antineoplastic Agents; Biochemistry; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Indolizines; Phenanthrenes; Phenanthrolines; Quinolizines; Structure-Activity Relationship