When skeletons of Win compounds were used as templates, computer-assisted drug design led to the identification of a novel series of imidazolidinone derivatives with significant antiviral activity against enterovirus 71 (EV 71), the infection of which had resulted in about 80 fatalities during the 1998 epidemic outbreak in Taiwan. In addition to inhibiting all the genotypes (A, B, and C) of EV 71 in the submicromolar to low micromolar range, compounds 1 and 8 were extensively evaluated against a variety of viruses, showing potent activity against coxsackievirus A9 (IC(50) = 0.47-0.55 microM) and coxsackievirus A24 (IC(50) = 0.47-0.55 microM) as well as moderate activity against enterovirus 68 (IC(50) = 2.13 microM) and echovirus 9 (IC(50) = 2.6 microM). Our SAR studies revealed that imidazolidinone analogues with an aryl substituent at the para position of the phenoxyl ring, such as compounds 20, 21, 27, 57, 58, and 61, in general exhibited the highest activity against EV 71. Among them, compound 20 and its corresponding hydrochloride salt 57, in terms of potency and selectivity index, appear to be the most promising candidates in this series for further development of anti-EV-71 agents. Preliminary results of the study on the mode of action by a time-course experiment suggest that test compounds 1 and 8 can effectively inhibit the virus replication at the early stages, referring to virus attachment or uncoating. This indicates that the surface protein may be the target for this type of compounds.
The molecular mechanisms for the anti-inflammatory activity of phenanthroindolizidine alkaloids were examined in an in vitro system mimicking acute inflammation by studying the suppression of lipopolysaccharide (LPS)/interferon-␥ (IFN␥)-induced nitric oxide production in RAW264.7 cells. Two of the phenanthroindolizidine alkaloids, NSTP0G01 (tylophorine) and NSTP0G07 (ficuseptine-A), exhibited potent suppression of nitric oxide production and did not show significant cytotoxicity to the LPS/IFN␥-stimulated RAW264.7 cells, in contrast to their respective cytotoxic effects on cancer cells. Tylophorine was studied further to investigate the responsible mechanisms. It was found to inhibit the induced protein levels of tumor necrosis factor-␣, inducible nitric-oxide synthase (iNOS), and cyclooxygenase (COX)-II. It also inhibited the activation of murine iNOS and COX-II promoter activity. However, of the two common responsive elements of iNOS and COX-II promoters, nuclear factor-B (NF-B) and adaptor protein (AP)1, only AP1 activation was inhibited by tylophorine in the LPS/IFN␥-stimulated RAW264.7 cells. Further studies showed that the tylophorine enhanced the phosphorylation of Akt and thus decreased the expression and phosphorylation levels of c-Jun protein, thereby causing the subsequent inhibition of AP1 activity. Furthermore, the tylophorine was able to block mitogen-activated protein/extracellular signal-regulated kinase kinase 1 activity and its downstream signaling activation of NF-B and AP1. Thus, NSTP0G01 exerts its anti-inflammatory effects by inhibiting expression of the proinflammatory factors and related signaling pathways.Phenanthroindolizidine alkaloids are a small group of compounds well known for their profound cytotoxic activity (Pettit et al., 1984;Abe et al., 1998;Staerk et al., 2000Staerk et al., , 2002 and thus have been exploited as potential therapeutic leads for anticancer agents (Staerk et al., 2002). These alkaloids were also shown to have anti-inflammatory, antiasthmatic, and antianaphylactic properties with consequences of altered immunological status in vivo (Gopalakrishnan et al., 1979(Gopalakrishnan et al., , 1980Raina and Raina, 1980;Ganguly and Sainis, 2001;Staerk et al., 2002). Although adenyl cyclase was stimulated in asthmatic patients' peripheral leukocytes treated with tylophorine (Raina and Raina, 1980), the molecular mechanisms of actions of these phenanthroindolizidine alkaloids for aforementioned functions are not clear as yet. Moreover, the analysis and knowledge of the structure-activity relationships of the phenanthroindolizidine alkaloids with their biological function are also scarce.Inflammation is a central feature of many pathological conditions and is mediated by a variety of soluble factors and cellular signaling events. For example, NF-B-dependent gene expression plays an important role in inflammatory responses and increases the expression of genes encoding cytokines and receptors involved in proinflammatory enzymes such as iNOS and COX-II (Giuliani et al....
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