Planta Med 2011; 77(5): 467-476
DOI: 10.1055/s-0030-1250478
Natural Product Chemistry
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Bioactive Natural, Biocatalytic, and Semisynthetic Tobacco Cembranoids

Hany N. Baraka1 , 2 , Mohammad A. Khanfar1 , John C. Williams1 , Emad M. El-Giar3 , Khalid A. El Sayed1
  • 1Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, USA
  • 2Current address: Department of Pharmacognosy, College of Pharmacy, Mansoura University, Mansoura, Egypt
  • 3Department of Chemistry, University of Louisiana at Monroe, Monroe, Louisiana, USA
Further Information

Publication History

received July 10, 2010 revised Sept. 19, 2010

accepted October 5, 2010

Publication Date:
03 November 2010 (online)

Abstract

The two major Nicotiana tabacum tobacco cembranoids, (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its C-4 epimer, exhibit a wide range of interesting biological activities. Although the tumorigenesis inhibition activity of tobacco cembranoids have been known since the mid 1980′s, only a limited number of investigations have targeted their optimization and structure-activity relationship. This study reports the isolation of the new (1S,2E,4S,6E,8S,11E)-2,6,11-cembratriene-8-O-methyl-4,8-diol (3) and the known (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4-O-methyl-4,6-diol (2) from fresh N. tabacum leaves. Cembranoid 2 showed good anti-migratory activity against prostate cancer cell lines, and was therefore subjected to microbial transformation and semisynthetic optimization studies. Biotransformation of 2 using the fungal strains Cunninghamella NRRL 5695 and Mucor ramannianus ATCC 9628 afforded new (4 and 5) and known (6 and 7) metabolites. Semisynthetic esterification, oxidation, epoxidation, and reaction with Lawesson's reagent afforded the new products 814. Cembranoid 2 and its epoxidation product 9 showed potent anti-migratory activities against the highly metastatic human prostate cancer cell lines PC-3M-CT+ (spheroid disaggregation assay) and PC-3 (wound-healing assay).

References

  • 1 Wahlberg I, Enzell C R. Tobacco cembranoids.  Beitrage zur Tabakforschung International. 1984;  12 93-104
  • 2 Eklund A M, Hatanaka S I, Wahlberg I. Progress in the chemistry of organic natural products. Wien, New York; Springer Verlag 1992: 143-293
  • 3 Dauben W G, Thiessen W E, Resnick P R. Cembrene, a 14-membered ring diterpene hydrocarbon.  J Am Chem Soc. 1962;  84 2015-2016
  • 4 Wahlberg I, Eklund A M. Trends in flavour research. Oxford; Elsevier Science B.V. 1994: 449-462
  • 5 Bylov A, Brummer U, Hass W, Seehofer F, Heemann V Z. New cembranoids from tobacco.  Naturforsch. 1983;  38c 515-516
  • 6 Pham N B, Butler M S, Quinn R J. Naturally occurring cembranes from an Australian Sarcophyton species.  J Nat Prod. 2002;  65 1147-1150
  • 7 Olsson E, Berg J E, Wahlberg I. Eight new cembranoids from tobacco-structural elucidation and conformational studies.  Tetrahedron. 1993;  49 4975-4992
  • 8 Olsson E, Holth A, Kumlin E, Bohlin L, Wahlberg I. Structure-related inhibiting activity of some tobacco cembranoids on the prostaglandin synthesis in vitro.  Planta Med. 1993;  59 293-295
  • 9 Saito Y, Takazawa H, Konishi S, Yoshida D, Mizusaki S. Identification of cembratriene-4,6-diol as antitumor-promoting agent from cigarette smoke condensate.  Carcinogenesis. 1985;  6 1189-1194
  • 10 El Sayed K A, Laphookhieo S, Baraka H N, Yousaf M, Hebert A, Bagaley D, Rainey F A, Muralidharan A, Thomas S, Shah G V. Biocatalytic and semisynthetic optimization of the anti-invasive tobacco (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol.  Bioorg Med Chem. 2008;  16 2886-2893
  • 11 Pagan O R, Rowlands A L, Fattore A L, Coudron T, Urban K R, Bidja A H, Eterovic V A. A cembranoid from tobacco prevents the expression of nicotine-induced withdrawal behavior in planarian worms.  Eur J Pharmacol. 2009;  615 118-124
  • 12 Smith R V, Rosazza J P. Microbial models of mammalian metabolism. Aromatic hydroxylation.  Arch Biochem Biophys. 1974;  161 551-558
  • 13 Clark A M, McChesney J D, Hufford C D. The use of microorganisms for the study of drug metabolism.  Med Res Rev. 1985;  5 231-251
  • 14 Thayer A N. Enzymes at work.  Chem Eng News. 2006;  84 14-25
  • 15 El Sayed K A, Hamann M T, Waddling C A, Jensen C, Lee S K, Dunstan C A, Pezzuto J M. Structurally novel bioconversion products of the marine natural product sarcophine effectively inhibit JB6 cell transformation.  J Org Chem. 1998;  63 7449-7455
  • 16 El Sayed K A, Laphookhieo S, Yousaf M, Prestridge J A, Shirode A B, Wali V B, Sylvester P W. Semisynthetic and biotransformation studies of (1S,2E,4S,6R,7E,-11E)-2,7,11-cembratriene-4,6-diol.  J Nat Prod. 2008;  71 117-122
  • 17 Wahlberg I, Eklund A M. Cembranoids, pseudopteranoids and cubitanoids of natural occurrence. Herz W, Kirby GW, Moore RE, Steglich W, Tamm CH Progress in the chemistry of organic natural products, Vol. 59. Wien, New York; Springer-Verlag 1992: 141-294
  • 18 Saito Y, Tsujino Y, Kaneko H, Yoshida D, Mizusaki S. Inhibitory effects of cembratriene-4,6-diol derivatives on the induction of Epstein-Barr virus early antigen by 12-O-tetradecanoylphorbol-13-acetate.  Agric Biol Chem. 1987;  51 941-943
  • 19 El Sayed K A, Sylvester P W. Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids.  Expert Opin Investig Drugs. 2007;  16 877-887
  • 20 Thomas S, Chigurupati S, Anbalagan M, Shah G V. Calcitonin increases tumorigenicity of prostate cancer cells: evidence for the role of protein kinase A and urokinase-type plasminogen receptor.  Mol Endocrinol. 2006;  20 1894-1911
  • 21 Thomas S, Chiriva-Internati M, Shah G V. Calcitonin receptor-stimulated migration of prostate cancer cells is mediated by urokinase receptor-integrin signaling.  Clin Exp Metastasis. 2007;  24 363-377
  • 22 Shah G V, Muralidharan A, Thomas S, Gokulgandhi M, Mudit M, Khanfar M, El Sayed K A. Identification of a small molecule(s) class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis.  Mol Cancer Ther. 2009;  8 509-520
  • 23 Mudit M, Khanfar M, Muralidharan A, Thomas S, Shah G V, El Sayed K A. Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products.  Bioorg Med Chem. 2009;  17 1731-1738
  • 24 Wahlberg I, Olsson E, Berg J E. Progress in Flavour Precursor Studies Proceeding International Conference. Carol Stream; Allured Publishing Corporation 1993: 83-95
  • 25 Forsblom I, Berg J E, Wahlberg I. Tobacco chemistry. 75. Two new cembratriene triols from tobacco.  Acta Chem Scand. 1993;  47 80-88
  • 26 Wahlberg I, Nishida T, Enzell C, Berg J E, Pilotti A M. Tobacco chemistry. 51. New cembranic diterpenoids from Greek tobacco.  Acta Chem Scand. 1980;  34 195-202
  • 27 Wahlberg I, Eklund A M, Vogt C, Enzell R C, Berg J E. Tobacco chemistry. 65. Two new 7,8-epoxycembranoids from tobacco.  Acta Chem Scand. 1986;  40 855-860
  • 28 Jesberger M, Davis T P, Barner L. Applications of Lawesson's reagent in organic and organometallic syntheses.  Synthesis. 2003;  13 1929-1958
  • 29 Shah G V, Noble M J, Austenfeld M, Weigel J, Deftos L J, Mebust W K, Winston K. Presence of calcitonin-like immunoreactivity (iCT) in human prostate gland: evidence for iCT secretion by cultured prostate cells.  Prostate. 1992;  21 87-97
  • 30 Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions.  FEBS Lett. 1997;  410 83-86
  • 31 Chien J, Ren Y, Wang Y Q, Bordelon W, Thompson E, Davis R, Rayford W, Shah G. Calcitonin is a prostate epithelium-derived growth stimulatory peptide.  Mol Cell Endocrinol. 2001;  181 69-79
  • 32 Lu K V, Jong K A, Rajasekaran A K, Cloughesy T F, Mischel P S. Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line.  Lab Invest. 2004;  84 8-20
  • 33 Herren B, Garton K J, Coats S, Bowen-Pope D F, Ross R, Raines E W. ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions.  Exp Cell Res. 2001;  271 152-160
  • 34 Cascone I, Giraudo E, Caccavari F, Napione L, Bertotti E, Collard J G, Serini G, Bussolino F. Temporal and spatial modulation of Rho GTPases during in vitro formation of capillary vascular network: Adherens junctions and myosin light chain as targets of Rac1 and RhoA.  J Biol Chem. 2003;  278 50702-50713

Dr. Khalid A. El Sayed

Department of Basic Pharmaceutical Sciences
College of Pharmacy
University of Louisiana at Monroe

1800 Bienville Drive

Monroe, LA 71201

USA

Phone: +1 31 83 42 17 25

Fax: +1 31 83 42 17 37

Email: elsayed@ulm.edu