Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

Abstract

Lignans are phenylpropanoid dimers distributed very widely in the plant kingdom. There are various kinds of lignan depending on the mode of dimerization of phenylpropanoid. Gomisin is a dibenzocyclooctadiene-type lignan compound and a component of Schizandra fruit extracts (30-32, 70). There are various types of gomisins, A, B, C, D, E, F, G, J, and N; some possess central nervous system depressant, analgesic, antitussive, and/or Ca antagonist activities (42, 69). As for the antiviral activities of lignans, it has been reported that tetrahydronaphthalene-type lignans have selective inhibitory activities on herpes simplex virus and cytomegalovirus (41, 43) and that dibenzylbutanolide-type lignans have an inhibitory effect on human immunodeficiency virus (HIV) replication (63). However, the ratio of toxic dose to effective dose (selective index) of dibenzylbutanolide-type lignan was no more than 5, suggesting that this could not be used as a clinically effective anti-HIV agent.In continuation of our search for anti-HIV agents (19, 20, 26, 52), we report in this paper new gomisin J derivatives which have potent anti-HIV activities with much higher selective indices than that of dibenzylbutanolide-type lignan. The highest selective index among gomisin J derivatives was over 300. MATERIALS AND METHODSChemicals. Gomisin J was isolated as previously described (32). Halogenated derivatives (Fig. 1) of gomisin J were synthesized from gomisin J by using halogenizing agents such as N-bromosuccinimide. Detailed descriptions of synthesis and characterization will be published elsewhere. Structures of pure, newly synthesized compounds were determined by nuclear magnetic resonance and infrared analyses. These compounds were kindly provided by Tanaka, Tsumura Central Research Institute, Ibaraki, Japan. 3Ј-Azido-3Ј-deoxythymidine (AZT) and 2Ј,3Ј-ddC were purchased from Sigma Chemical Co. ). These cells were grown in 25 mM HEPES (N-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid)-buffered RPMI 1640 (GIBCO) supplemented with 10% fetal calf serum, 100 U of penicillin per ml, 100 g of streptomycin per ml, and 0.25 g of amphotericin B per ml. At this concentration, amphotericin B is effective as an antimycotic in tissue culture but has no inhibitory activity for HIV replication (50, 64).

Simultaneous quantification of four active schisandra lignans from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using liquid chromatography/mass spectrometry

“…them have been isolated by now [3,4] in which the most abundant ingredients include schisandrin, schisantherin A, deoxyshisandrin and ␥-schisandrin. Schisandra lignans have been shown to have various biological activities, such as hepatoprotective effect [5], potent antioxidative property [6], anticarcinogenic activity through the activation of key liver enzymes [7] and strong inhibiting effect on human immunodeficiency virus (HIV) [8] reported recently. Moreover, Schisandra chinensis has also been shown to increase the physical performance and recovery rates in race horses [9][10][11].…”

Separation procedures applicable to lignan analysis

“…The results show that the methylenedioxy group and the dibenzocyclooctadiene skeleton is an important structural determinant of the protective effect [22]. In the course of search for natural anti-AIDS agents, it was found that some dibenzocyclooctadiene lignans significantly inhibit the HIV replication [23,24]. Some of them have also cytostatic, antiinflammatory, antiulcer, vasorelaxant and neuroleptic activities [25].…”

On-line continuous sampling dynamic microwave-assisted extraction coupled with high performance liquid chromatographic separation for the determination of lignans in Wuweizi and naphthoquinones in Zicao

“…Lignans are the major effective components in Wuweizi, which are beneficial to the protection of the livers and cardiovascular systems [2][3][4][5][6]. The halogenated lignans have inhibiting effect on human immunodeficiency virus (HIV) [7]. The content of schisandrin A is considered as the quality criterion of Wuweizi.…”