Journal Mobile Options
Table of Contents
Vol. 58, No. 4, 2012
Issue release date: November 2012
Chemotherapy 2012;58:299–307

New Anthraquinone Derivatives as Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Function

Esposito F. · Corona A. · Zinzula L. · Kharlamova T. · Tramontano E.
Department of Life and Environmental Sciences, University of Cagliari, Monserrato, Italy

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: The degradative activity of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), termed ribonuclease H (RNase H), which hydrolyzes the RNA component of the heteroduplex RNA:DNA replication intermediate, is an excellent target for drug discovery. Anthraquinones (AQs) and their derivatives, which are common secondary metabolites occurring in bacteria, fungi, lichens and a large number of families in higher plants, have been reported to have several biological activities including that of inhibiting HIV-1 RT activities in biochemical assays. Methods: We have assayed new AQ derivatives on HIV-1 RNase H activities in biochemical assays. Results: Six series of new AQ derivatives with various substituents at positions 1, 2, 3 and 4 of the AQ ring were tested, and new analogs able to inhibit HIV-1 RT-associated RNase H activity in the low micromolar range were found. Conclusions: Our results demonstrate that AQ derivatives are promising anti-RNase H inhibitors.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Engelman A, Cherepanov P: The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 2012;10:279–290.
  2. Esposito F, Corona A, Tramontano E: HIV-1 reverse transcriptase still remains a new drug target: structure, function, classical inhibitors and new inhibitors with innovative mechanisms of actions. Mol Biol Int 2012;2012:586401.
  3. Tramontano, E: HIV-1 RNase H: Recent progress in an exciting, yet little explored, drug target. Mini Rev Med Chem 2006;6:727–737.
  4. Tramontano E, Di Santo R: HIV-1 RT-associated RNase H function inhibitors: recent advances in drug development. Curr Med Chem 2010;17:2837–2853.
  5. Huang HS, Chiou JF, Fong Y, Hou CC, Lu YC, Wang JY, Shih JW, Pan YR, Lin JJ: Activation of human telomerase reverse transcriptase expression by some new symmetrical bis-substituted derivatives of the anthraquinone. J Med Chem 2003;46:3300–3307.
  6. Tan JH, Zhang QX, Huang ZS, Chen Y, Wang XD, Gu LQ, Wu JY: Synthesis, DNA binding and cytotoxicity of new pyrazole emodin derivatives. Eur J Med Chem 2006;41:1041–1047.
  7. Wheate NJ, Brodie CR, Collins JG, Kemp S, Aldrivch-Wright JR: DNA intercalators in cancer therapy: organic and inorganic drugs and their spectroscopic tools of analysis. Mini Rev Med Chem 2007;6:627–648.

    External Resources

  8. Huang Q, Lu G, Shen HM, Chung MC, Onq CN: Anticancer properties of anthraquinones from rhubarb. Med Res Rev 2007;27:609–630.
  9. Bernard DL, Huffman JH, Morris JLB, Wood SG, Huges BG, Sidwell RW: Evaluation of the antiviral activity of anthraquinones, anthrones and anthraquinone derivatives against human cytomegalovirus. Antiviral Res 1992;17:63–77.
  10. Bernard DL, Firbairn DW, O’Neill KL, Gage TL, Sidwell RW: Anti-human cytomegalovirus activity and toxicity of sulfonated anthraquinones and anthraquinone derivatives. Antiviral Res 1995;28:317–329.
  11. Semple SJ, Pyke SM, Reynolds GD, Flower FLP: In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus. Antiviral Res 2001;49:169–178.
  12. Shuangsuo D, Zhengguo Z, Yunru C, Xin Z, Baofeng W, Lichao Y, Yan’an C: Inhibition of the replication of hepatitis B virus in vitro by emodin. Med Sci Monit 2006;12:302–306.
  13. Li Z, Li LJ, Sun Y, Li J: Identification of natural compounds with anti-hepatitis B virus activity from Rheum palmatum L. ethanol extract. Chemotheraphy 2007;53:320–326.
  14. Esimone CO, Grunwald T, Nworu CS, Kuate S, Proksch P, Überla K: Broad spectrum antiviral fractions from the lichen Ramalina farinacea (L.) Ach. Chemotherapy 2009;55:119–126.
  15. Schinazi RF, Chu CK, Babu JR, Oswald BJ, Saalmann V, Cannon DL, Eriksson BF, Nasr M: Anthraquinones as a new class of antiviral agents against human immunodeficiency virus. Antiviral Res 1990;13:265- 272.
  16. Higuchi H, Mori K, Kato A, Ohkuma T, Endo T, Kaji H, Kaji A: Antiretroviral activities of anthraquinones and their inhibitory effects on reverse transcriptase. Antiviral Res 1991;15:205–216.
  17. Esposito F, Kharlamova T, Distinto S, Zinzula L, Cheng YC, Dutschman G, Floris G, Markt P, Corona A, Tramontano E: Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases. FEBS J 2011;278:1444–1457.
  18. Kharlamova T, Esposito F, Zinzula L, Floris G, Cheng Y-C, Dutschman GE, Tramontano E: Inhibition of HIV-1 ribonuclease H activity by novel frangula–emodine derivatives. Med Chem 2009;5:398–410.

    External Resources

  19. Farnet CM, Wang B, Lipford JR, Bushman FD: Differential inhibition of HIV-1 preintegration complexes and purified integrase protein by small molecules. Proc Natl Acad Sci USA 1996;93:9742–9747.
  20. Tramontano E, Esposito F, Badas R, Di Santo R, Costi R, La Colla P: 6-[1-(4-Fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro. Antiviral Res 2005;65:117–124.
  21. Tramontano E, Kharlamova T, Zinzula L, Esposito F: Effects of new quinizarin derivatives on both HCV NS5B RNA polymerase and HIV-1 reverse transcriptase associated ribonuclease H activities. J Chemother 2011;23:273- 276.
  22. Tramontano E, Cheng YC: HIV-1 reverse transcriptase inhibition by a dipyridodiazepinone derivative: BI-RG-587. Biochem Pharmacol 1992;43:1371–1376.
  23. Artico M, Massa S, Mai A, Marongiu ME, Piras G, Tramontano E, La Colla P: 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs): a new class of specific inhibitors of human immunodeficiency virus type 1. Antiviral Chem Chemother 1993;4:361–368.
  24. Mellors J, Im GJ, Tramontano E, Winkler SR, Medina DJ, Dutschman GE, Bazmi HZ, Piras G, Gonzales CJ, Cheng YC: A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4, 5, 1- jk][1, 4]benzodiazepin-2(1H)-thione (TIBO R82150). Mol Pharmacol 1993;43:11–16.
  25. Suchaud V, Bailly F, Lion C, Tramontano E, Esposito F, Corona A, Christ F, Debyser Z, Cotelle P: Development of a series of 3-hydroxyquinolin-2(1H)-ones as selective inhibitors of HIV-1 reverse transcriptase associated RNase H activity. Bioorg Med Chem Lett 2012;22:3988–3992.
  26. Distinto S, Esposito F, Kirchmair J, Cardia MC, Gaspari M, Maccioni E, Alcaro S, Markt P, Wolber G, Zinzula L, Tramontano E: Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach. Eur J Med Chem 2012;50:1–14.

    External Resources

  27. Starnes MC, Cheng YC: Human immunodeficiency virus reverse transcriptase-associated RNase H activity. J Biol Chem 1989;264:7073–7077.
  28. Himmel DM, Sarafinos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, Clark AD, Knight JL, Julias JG, Clark PK, Krogh-Jespersen K, Levy RM, Hughes SH, Parniak MA, Arnold E: HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphtyl hydrazone bound at a novel site. ACS Chem Biol 2006;1:702–712.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50