Sesquiterpenes and Butenolides, Natural Anti-HIV Constituents from Litsea verticillata

Abstract

In a continuing investigation, six sesquiterpenes, as well as five butenolides were isolated from the leaves and twigs of Litsea verticillata Hance (Lauraceae). Among the isolates, three were determined to be new sesquiterpenes: isolitseanes A (1), B (2) and C (3); three known sesquiterpenes were identified as oxyphyllenodiol B (4), 1,2,3,4-tetrahydro-2,5-dimethyl-8-(1-methylethyl)-1,2-naphthalenediol (5), and chromolaevanedione (6). The butenolides include the novel litseabutenolide (9) and four known compounds: 3-epi-litsenolide D₂ (7), cis-listenolide D₁ (8), 4-hydroxy-2-methylbut-2-enolide (10), and hydroxydihydrobovolide (11). Isolates 2, 4, 5, 7, 9, 10 and 11 were found to inhibit HIV-1 replication in a green fluorescent protein (GFP)-based reporter cell line (HOG.R5) with IC₅₀ values of 38.1, 54.6, 91.0, 9.9, 40.3, 129.8, and 122.7 μM, respectively. Structure elucidation and identification were based on spectroscopic means including 1D and 2D NMR analyses.

Litsea verticillata - Lauraceae - anti-HIV activity - bioassay-directed fractionation - sesquiterpenes - butenolides

References

• 1 Hoang V D, Tan G T, Zhang H J, Tamez P A, Hung N V, Cuong N M. et al . Natural anti-HIV agents. Part I. (+)-Demethoxyepiexcelsin and verticillatol from Litsea verticillata .  Phytochemistry. 2002;  59 325-9
• 2 Zhang H J, Tan G T, Hoang V D, Hung N V, Cuong N M, Soejarto D D. et al . Natural anti-HIV agents. Part II. Litseaverticillol A, a prototypic litseane sesquiterpene from Litsea verticillata .  Tetrahedron Lett. 2001;  42 8587-91
• 3 Zhang H J, Tan G T, Hoang V D, Hung N V, Cuong N M, Soejarto D D. et al . Natural anti-HIV agents. Part III. Litseaverticillols A - H, novel sesquiterpenes from Litsea verticillata .  Tetrahedron. 2003;  59 141-8
• 4 Zhang H J, Tan G T, Santarsiero B D, Mesecar A D, Hung N V, Cuong N M. et al . New sesquiterpenes from Litsea verticillata .  J Nat Prod. 2003;  66 609-15
• 5 Tan G T, Honnen W J, Kayman S C, Pinter A. A sensitive microtiter infectivity assay for macrophage-tropic and primary isolates of HIV-1 based on the transactivation of a stably integrated gene for the green fluorescent protein. The 9th National Cooperative Vaccine Development Group (NCVDG) Meeting 1997: Advances in AIDS Pathogenesis and Preclinical Vaccine Development. NIH Bethesda, Maryland; May 4 - 7
• 6 Weislow O S, Kiser R, Fine D L, Bader J, Shoemaker R H, Boyd M R. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity.  J National Cancer Inst. 1989;  81 577-86
• 7 Muraoka O, Fujimoto M, Tanabe G, Kubo M, Minematsu T, Matsuda H. et al . Absolute stereostructures of novel norcadinane- and trinoreudesmane-type sesquiterpenes with nitric oxide production inhibitory activity from Alpinia oxyphylla .  Bioorg & Med Chem Lett. 2001;  11 2217-20
• 8 Kuo Y H, Yu M T. Four new sesquiterpenes from the heartwood of Juniperus formosana var. concolor .  Chem Pharm Bull. 1999;  47 1017-9
• 9 Misra L N, Jakupovic J, Bohlmann F, Schmeda-Hirschmann G. Isodaucane derivatives, norsesquiterpenes and clerodanes from Chromolaena laevigata .  Tetrahedron. 1985;  41 5353-6
• 10 Lee S S, Chang S M, Chen C H. Chemical constituents from Alseodaphne andersonii .  J Nat Prod. 2001;  64 548-51
• 11 Niwa M, Iguchi M, Yamamura S. Isolation and structure of obtusilactone.  Tetrahedron Lett. 1975;  16 1539-42
• 12 Takabe K, Yoda H, Tanaka M, Sugimoto M, Ishioka T, Miyazaki A. Preparation of butenolide derivatives as intermediates for perfumes and biologically active compounds (Japan).  Jap Kokai Tokkyo Koho. 1990;  JP2218672 5 pp
• 13 van der Merwe J P, Garbers C F. Photochemical oxidation of 3-methylfuran.  J South African Chem Inst. 1964;  17 149-50
• 14 Chen L, Izumi S, Ito D I, Iwaeda T, Utsumi R, Hirata T. Secretion of allelochemicals from the cultured suspension cells of Marchantia polymorpha . Chem Lett 1996: 205-6
• 15 Nozoe S, Goi M, Morisaki N. Structure of cyclonerodiol.  Tetrahedron Lett. 1970;  11 1293-6
• 16 Chang K C, Duh C Y, Chen I S, Tsai I L. A cytotoxic butenolide, two new dolabellane diterpenoids, a chroman and a benzoquinol derivative from Formosan Casearia membranacea .  Planta Med. 2003;  69 667-72
• 17 Tuchinda P, Udchachon J, Reutrakul V, Santisuk T, Taylor W C, Farnsworth N R. et al . Bioactive butenolides from Melodorum fruticosum .  Phytochemistry. 1991;  30 2685-9
• 18 Soejarto D D, Gyllenhaal C, Regalado J C, Pezzuto J M, Fong H HS, Tan G T. et al . Studies on biodiversity of Vietnam and Laos: the UIC-based ICBG program.  Pharm Biol. 1999;  37 (Supplement) 100-13
• 19 Coates J AV, Cammack N, Jenkinson H J, Mutton I M, Pearson B A, Storer R. et al . The separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189) both inhibit HIV replication in vitro .  Antimicrob Agents Chemother. 1992;  36 202-5