N-Acetylphenylisoserinates of Lactarius Sesquiterpenoid Alcohols - Cytotoxic, Antiviral, Antiproliferative and Immunotropic Activities in vitro

Abstract

In the present study a new group of derivatives of both paclitaxel and Lactarius sesquiterpenes, the N-acetylphenylisoserinates of Lactarius sesquiterpenoid alcohols, was tested for antiviral, cytotoxic, antiproliferative and immunotropic activities in vitro. Among the 13 compounds tested two, isolactarorufin 8-[N-acetyl-(2′R,3′S)-3′-phenylisoserinate] and 3-O-ethylfurandiol 8-[N-acetyl-(2′R,3′S)-3′-phenylisoserinate] inhibited Herpes simplex virus type 1 (HSV-1) replication at low cytotoxic concentrations. Selectivity indices were: > 12.2 and > 106.4, respectively. Both compounds decreased also the number of cell divisions. Mitotic indices of the cells submitted to these compounds were: 96/2000 and 48/1000, respectively, in comparison with control (169/2000). It seems that the antimitotic action of the compounds may be associated with their antiviral activity. Moreover, isolactarorufin 8-[N-acetyl-(2′R,3′S)-3′-phenylisoserinate] inhibited PHA-induced T lymphocyte proliferation.

Abbreviations

MEM:minimum essential medium

FCS:foetal calf serum

MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

CC₅₀:50 % cytotoxic concentration

HSV-1_MC:Herpes simplex virus 1 McIntyre strain

TCID₅₀:50 % tissue culture infective dose

CPE:cytopathic effect

IC₅₀:50 % inhibitory concentration

PBMCs:peripheral blood mononuclear cells

PHA:phytohemagglutinin

Lactarius - Russulaceae - sesquiterpenes - paclitaxel - antiviral activity - lymphocyte proliferation - mitosis

References

• 1 Efferth T, Marschall M, Wang X, Huong S M, Hauber I, Olbrich A. et al . Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses.  J Mol Med. 2002;  80 233-42
• 2 Sotanaphun U, Lipipun V, Suttisri R, Bavovada R. A new antiviral and antimicrobial sesquiterpene from Glyptopetalum sclerocarpum .  Planta Med. 1999;  65 257-8
• 3 Wright A E, Rueth S A, Cross S S. An antiviral sesquiterpene hydroquinone from the marine sponge Strongylophora hartmani .  J Nat Prod. 1991;  54 1108-11
• 4 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
• 5 Tziveleka L A, Vagias C, Roussis V. Natural products with anti-HIV activity from marine organisms.  Curr Top Med Chem. 2003;  3 1512-35
• 6 Jin H Z, Hwang B Y, Kim H S, Lee J H, Kim Y H, Lee J J. Anti-inflammatory constituents of Celastrus orbiculatus inhibit the NF-κB activation and NO production.  J Nat Prod. 2002;  65 89-91
• 7 Sosa S, Tubaro A, Kastner U, Glasl S, Jurenitsch J, Della Loggia R. Topical anti-inflammatory activity of a new germacrane derivative from Achillea pannonica .  Planta Med. 2001;  67 654-8
• 8 Duan H, Takaishi Y, Momota H, Ohmoto Y, Taki T, Jia Y. et al . Immunosuppressive sesquiterpene alkaloids from Tripterygium wilfordii .  J Nat Prod. 2001;  64 582-7
• 9 Zhao W, Ye Q, Tan X, Jiang H, Li X, Chen K. et al . Three new sesquiterpene glycosides from Dendrobium nobile with immunomodulatory activity.  J Nat Prod. 2001;  64 1196-200
• 10 Kobus M, Przybylski M, Daniewski W, Krawczyk E, Luczak M. Biological activities of sesquiterpenes of Lactarius origin [in Polish].  Probl Hig. 2001;  71 134-9
• 11 Knox S N, Robinson J B, Im D D, Logan L, Rosenshein N B. The use of paclitaxel and cisplatin in a patient with epithelial ovarian cancer and human immunodeficiency virus.  Gynecol Oncol. 2000;  76 118-22
• 12 Gupta ML J r, Bode C J, Georg G I, Himes R H. Understanding tubulin-taxol interactions: mutations that impart taxol binding to yeast tubulin.  Proc Natl Acad Sci USA. 2003;  100 6394-7
• 13 White C M, Martin B K, Lee L F, Haskill J S, Ting J P. Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T lymphocytes, and breast cancer cells.  Cancer Immunol Immunother. 1998;  46 104-12
• 14 Puente J, Diaz M, Salas M A, Miranda , Gaggero A, Wolf M E. et al . Studies of natural killer cell activity in a drug-free, healthy population. Response to a challenge with taxol, estramustine and lipopolysaccharide.  Int J Clin Pharmacol Ther. 1995;  33 457-61
• 15 Kim S E, Kim Y H, Kim Y C, Lee J J. Torilin, a sesquiterpene from Torilis japonica, reverses multidrug-resistance in cancer cells.  Planta Med. 1998;  64 332-4
• 16 Hammond L A, Hilsenbeck S G, Eckhardt S G, Marty J, Mangold G, MacDonald J R. et al . Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model.  Eur J Cancer. 2000;  36 2430-6
• 17 Patel N M, Nozaki S, Shortle N H, Bhat-Nakshatri P, Newton T R, Rice S. et al . Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide.  Oncogene. 2000;  19 4159-69
• 18 Krawczyk E, Luczak M, Kobus M, Banka D, Daniewski W. Antiviral activity of N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols in vitro .  Planta Med. 2003;  69 552-4
• 19 Krawczyk E, Luczak M, Kniotek M, Majewska A, Kawecki D, Nowaczyk M. Immunomodulatory activity and influence on mitotic divisions of N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols in vitro .  Planta Med. 2005;  71 819-24
• 20 Krawczyk E, Luczak M, Kniotek M, Nowaczyk M. Cytotoxic, antiviral (in vitro and in vivo), immunomodulatory activity and influence on mitotic divisions of three taxol derivatives: 10-deacetyl-baccatin III, methyl (N-benzoyl-(2′R,3′S)-3′-phenylisoserinate) and N-benzoyl-(2′R,3′S)-3′-phenylisoserine.  J Pharm Pharmacol. 2005;  57 791-7
• 21 Barycki R, Gumulka M, Masnyk M, Daniewski W M, Kobus M, Luczak M. Synthesis of N-acetyl-3-phenylisoserinates of sesquiterpenoid alcohols of Lactarius origin.  Collect Czech Chem Commun. 2002;  67 75-82
• 22 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.  J Immunol Methods. 1983;  65 55-63
• 23 Reed L J, Muench M A. A simple method of estimating fifty percent end points.  Am J Hyg. 1938;  27 483-7
• 24 De Clercq E. Strategies in the design of antiviral drugs.  Nat Rev Drug Discov. 2002;  1 13-25
• 25 Morfin F, Thouvenot D. Herpes simplex virus resistance to antiviral drugs.  J Clin Virol. 2003;  26 29-37
• 26 Hammonds T R, Denyer S P, Jackson D E, Irving W L. Studies to show that with podophyllotoxin the early replicative stages of Herpes simplex virus type 1 depend upon functional cytoplasmic microtubules.  J Med Microbiol. 1996;  45 167-72
• 27 Norrild B, Lehto V P, Virtanen I. Organization of cytoskeleton elements during Herpes simplex virus type 1 infection of human fibroblasts: an immunofluorescence study.  J Gen Virol. 1986;  67 97-105
• 28 Cuthbert J A, Shay J W. Microtubules and lymphocyte responses: effect of colchicine and taxol on mitgen-induced human lymphocyte activation and proliferation.  J Cell Physiol. 1983;  116 127-34