Six morphinane alkaloids, cephasamine (3), cephakicine (4), tannagine (6), 14-episinomenine (7), FK-3000 (8), and sinoacutine (9), and five hasubanane alkaloids, cephatonine (5), cepharamine (10), aknadinine (11), aknadicine (12), and aknadilactam (13), were isolated from the tuber of Stephania cepharantha Hayata (Menispermaceae) cultivated in Japan. Three of these (3−5) were new alkaloids. Structures were spectroscopically determined by comparison of their 1H and 13C NMR data with that of cephamonine (1), cephamuline (2), and other known alkaloids (6−13).

Cepharanthine (12- O-methyl cepharanoline) is a plant alkaloid and has been shown to inhibit tumour necrosis factor-α- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in the chronically infected promonocytic cell line, U1. Its mechanism of action is considered to be the inhibition of nuclear factor κB, a potent inducer of HIV-1 gene expression. In this study, we have synthesized 96 derivatives of cepharanoline, including cepharanthine, and examined their inhibitory effects on HIV-1 replication in U1 cells. Among the 12- O-alkyl derivatives, cepharanthine proved to be the most active, and the activity decreased as the length of the alkyl chain increased. All of the 12- O-acyl derivatives were totally inactive, while a few 12- O-carbamoyl derivatives displayed modest activity. Since 12- O-ethyl derivatives were found to be as active as cepharanthine against HIV-1 replication, we further synthesized various 12- O-ethyl derivatives of cepharanoline. Among the derivatives, five proved to be more active inhibitors than cepharanthine, and the most active compound was 12- O-ethylpiperazinyl cepharanoline. The 50% effective concentrations of this compound and cepharanthine were 0.0041 and 0.028 μg/ml (0.0060 and 0.046 μM), respectively.

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By screening water and MeOH extracts of 30 Chinese medicinal plants for their anti-herpes simplex virus (HSV)-1 activity, a MeOH extract of the root tubers of Stephania cepharantha HAYATA showed the most potent activity on the plaque reduction assay with an IC50 value of 18.0 microg/ml. Of 49 alkaloids isolated from the MeOH extract, 17 alkaloids were found to be active against HSV-1, including 13 bisbenzylisoquinoline, 1 protoberberine, 2 morphinane and 1 proaporphine alkaloids, while benzylisoquinoline and hasubanane alkaloids were inactive. Although N-methylcrotsparine was active against HSV-1, as well as HSV-1 thymidine kinase deficient (acyclovir resistant type, HSV-1 TK-) and HSV-2 (IC50 values of 8.3, 7.7 and 6.7 microg/ml, respectively), it was cytotoxic. FK-3000 was found to be the most active against HSV-1, HSV-1 TK- and HSV-2 (IC50 values of 7.8, 9.9 and 8.7 microg/ml) with in vitro therapeutic indices of 90, 71 and 81, respectively. FK-3000 was found to be a promising candidate as an anti-HSV agent against HSV-1, acyclovir (ACV) resistant-type HSV-1 and HSV-2.

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The antiviral activity of a MeOH extract of Stephania cepharantha (root tubers), its CHCl3-soluble fraction (alkaloid fraction) and the major alkaloid FK-3000 (1) were investigated in BALB/c mice cutaneously infected with HSV-1 strain 7401H. At doses of 125 and 250 mg/kg body weight, p.o., the MeOH extract significantly delayed skin lesion on score 2 (vesicles in the local region), limited the development of further lesions on score 6 (mild zosteriform lesion) and prolonged the mean survival time of HSV-1 infected mice. After p.o. administration of the CHCl3-soluble fraction at doses of 25 and 50 mg/kg or FK-3000 (1) at 10 and 25 mg/kg, similar results were obtained. Although the alkaloid improved the survival of infected mice, it had a narrow therapeutic index.

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