Anti-HIV-1 Activity and Structure-Activity Relationship of Cepharanoline Derivatives in Chronically Infected Cells

Abstract

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.

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

“…In spite of a robust effect in latently infected cells, ACHP did not show a significant inhibitory effect in chronically infected A previous study of the effects of an NF-B inhibitor (4,46) against chronic HIV infection reported it to be ineffective in suppressing constitutive HIV-1 production, which is consistent with what we observed in this study. Hence, it is also possible that the cellular uptake or intracellular metabolism of ACHP is different in OM10.1 and MOLT4/III B cells.…”

“…HIV-1 replication is positively regulated by several cytokines, or T-cell activators, most of which act either completely or partially via NF-B (4,8,38). NF-B has been shown to regulate viral transcription via the two NF-B sites located in the HIV-1 long terminal repeat (LTR) enhancer region (44) and is further enhanced through synergism with Sp1 (34,49).…”

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

“…A cepharanthine analog, 12-O-ethylpiperazinylcepharanoline, that was the most active anti-HIV-1 compound among various tested cepharanthine derivatives, 14) was kindly provided by Dr. Baba (Kagoshima University). Agosterol A (AG-A) was isolated from a marine sponge (Spongia sp.)…”

Ethnomedicinal Antivirals: Scope and Opportunity

“…Solamargine and michellamine B, the glycoalkaloids of Solanum khasianum berries, has been shown to inhibit HIV, while berberine inhibited intestinal infections associated with AIDS [102]. Duan et al [103] reported that the pyridine alkaloid triptonine from Tripterygium hypoglaucum and a clinically used extract of T. wilfordii have potent anti-HIV activity [104], but matairesinol and harman from Symplocos setchuensis inhibited HIV replication [16]. The skimmianine isolated from the extract of Zanthoxylum chalybeum seed inhibited Edmonston and Swartz strains of measles virus [105].…”

“…Cepharanthine (Fig. 15.15), a biscoclaurine alkaloid isolated from a Chinese folklore plant Stephania cepharantha, inhibited HIV-1 replication by inhibiting kappa B, a potent inducer of HIV-1 gene expression [104] and displayed potent activity against SARS coronavirus, HSV-1, and coxsackie B3 (Table 15.1) along with antitumor and immunomodulating activity [111]. As cepharanthine had strong activity against both RNA and DNA viruses it may be a source of potential lead compounds for developing new antivirals.…”