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Tannins and Related Compounds as Anti-HIV Agents 1

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Natural Products as Antiviral Agents

Abstract

Four new tetragalloylquinic acids, 3,5-di-O-galloyl-4-O-digalloylquinic acid (2), 3,4-di-O-galloyl-5-O-digalloylquinic acid (3), 3-O-digalloyl-4,5-di-O-galloylquinic acid (4), and 1,3,4,5-tetra-O-galloylquinic acid (5), were isolated and characterized from a commercial tannic acid as a new class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitor. Compounds 2, 3 and 4 inhibit HIV RT activity 90, 89 and 84% at 100 μM and 73, 70 and 63% at 30 μM, respectively. Compounds 2–5 also inhibit the HIV growth in cells in the range of 61–70% with low cytotoxicity at 25 μM. The HIV cell growth inhibitory effects of these compounds at 25 μM and 6.25 μM (44–57%) are comparable to their effects against the HIV RT at 30 μM and 10 μM, respectively. The inhibitory effect of 3 against DNA polymerases indicates that the selective antiviral action of 3 is determined by more than its action with HIV RT.

Following the aforementioned discoveries, 51 tannins, including gallo-, ellagi- and condensed tannins, were evaluated for their inhibitory effect against HIV RT. The most potent inhibitors were found to be punicalin (32) and punicacortein-C (40) with ID50 of 8 and 5 μM, respectively. Several of the tannins including these were further examined for their anti-HIV activity. 1,3,4-Tri-O-galloylquinic acid (13), 3,5-di-O-galloylshikimic acid (16), 3,4,5-tri-O-galloylshikimic acid (17), punicalin (32) and punicalagin (33) inhibited HIV replication in infected H9 lymphocytes with little cytotoxicity. Preincubation of virus with tannins indicated that chebulagic acid (31) and punicalin (32) did not inactivate virus directly. However, 1,3,4-tri-O-galloylquinic acid (13) and 3,5-di-O-galloylshikimic acid (16) were more effective inhibitors under these conditions. Thus, in spite of their anti-RT activity, the mechanism by which tannins inhibit HIV may not be associated with this enzyme.

Structure-activity relationship studies among 32 related tannins have led to the synthesis and evaluation of a series of hexahydroxydiphenyl derivatives of ellagic acid as simple analogs of ellagitannins and inhibitors of HIV replication. Among these analogs, 2,2′-dimethoxy-3,3′,4,4′-tetrabenzyloxy-1,1′-diphenyl-6,6′-dimethanol (61) was found to be a potent inhibitor of HIV replication in infected H9 lymphocytes with little cytotoxicity. Preincubation of 61 with virions before infection also showed that there was no inhibition of HIV. This mechanism of HIV inhibition is different from those ellagitannins, such as 32, 33 and 40.

Anti-AIDS Agents 7.

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Authors and Affiliations

  1. Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Kuo-Hsiung Lee, Yoshiki Kashiwada, Makoto Nishizawa & Takashi Yamagishi

  2. Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan

    Gen-ichiro Nonaka & Itsuo Nishioka

  3. Cambridge Biotech Corporation, 1600 East Gude Drive, Rockville, Maryland, 20850, USA

    Anne J. Bodner & Robert E. Kilkuskie

  4. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, 06510, USA

    Yung-Chi Cheng

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  1. Kuo-Hsiung Lee
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  2. Yoshiki Kashiwada
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  3. Gen-ichiro Nonaka
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  6. Takashi Yamagishi
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  7. Anne J. Bodner
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Editors and Affiliations

  1. The University of Georgia, Athens, Georgia, USA

    Chung K. Chu

  2. Agricultural Research Service, United States Department of Agriculture, Athens, Georgia, USA

    Horace G. Cutler

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Lee, KH. et al. (1992). Tannins and Related Compounds as Anti-HIV Agents 1. In: Chu, C.K., Cutler, H.G. (eds) Natural Products as Antiviral Agents. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3414-3_4

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  • DOI: https://doi.org/10.1007/978-1-4615-3414-3_4

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