Molecular Diversity

, Volume 17, Issue 3, pp 573–593 | Cite as

Novel potential agents for ulcerative colitis by molecular topology: suppression of IL-6 production in Caco-2 and RAW 264.7 cell lines

  • María Galvez-Llompart
  • María del Carmen Recio Iglesias
  • Jorge Gálvez
  • Ramón García-Domenech
Full-Length Paper

Abstract

Ulcerative colitis (UC) is an immune-mediated chronic and relapsing intestinal inflammatory disease. Interleukin (IL)-6, a pro-inflammatory cytokine, plays a key role in the uncontrolled intestinal inflammatory process, which is a main characteristic of UC. In this work, a quantitative structure–activity relationship model based on molecular topology (MT) has been built up to predict the IL-6 mediated anti-UC activity. After an external validation of the model, a virtual screening of the MicroSource Pure Natural Products Collection and Sigma-Aldrich databases was carried out looking for potential new active compounds. From the entire set of compounds labeled as active by the model, four of them, namely alizarin-3-methylimino-N,N-diacetic acid (AMA), Calcein, (+)-dibenzyl-l-tartrate (DLT), and Ro 41-0960, were tested in vitro by determination of IL-6 production in two cell lines (RAW 264.7 and Caco-2). The results demonstrate that three of them were able to significantly reduce IL-6 levels in both cell lines and particularly one, namely Ro 41-0960. These results confirm MT’s efficacy as a tool for the selection of compounds potentially active in UC.

Graphical Abstract

Keywords

Interleukin-6 (IL-6) Quantitative structure–activity relationship (QSAR) Molecular topology Virtual screening RAW 264.7 (mouse leukemic monocyte macrophage cell line) Caco-2 (human epithelial colorectal adenocarcinoma cells) 

Notes

Acknowledgments

We thank the Ministerio de Economia y Competitividad, Spain (projects SAF2009-13059-C03-01 and SAF2009-13059-C03-02) for support of this study. M Galvez-Llompart acknowledges the Atraccio de talents Fellowship provided by the University of Valencia to carry out this study.

Supplementary material

11030_2013_9458_MOESM1_ESM.doc (210 kb)
Supplementary material 1 (doc 210 KB)

References

  1. 1.
    Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterol 126:1504–1517. doi: 10.1053/j.gastro.2004.01.063 Google Scholar
  2. 2.
    Fantini MC, Pallone F (2008) Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets 9:375–380. doi: 10.2174/138945008784221206 PubMedCrossRefGoogle Scholar
  3. 3.
    Eaden J (2004) Review article: colorectal carcinoma and inflammation bowel disease. Alim Pharmacol Ther Suppl 4:24–30CrossRefGoogle Scholar
  4. 4.
    Gálvez-Llompart M, Recio MC, García-Domenech R (2011) Topological virtual screening: a way to find new compounds active in ulcerative colitis by inhibiting NF-\(\kappa \)B. Mol Divers 15:917–926. doi:  10.1007/s11030-011-9323-4 PubMedCrossRefGoogle Scholar
  5. 5.
    Matsumoto S, Hara T, Hori T, Mitsuyama M, Nagaoka M, Tomiyasu N, Suzuki N, Sata M (2005) Probiotic Lactobacillus-induced improvement in murine chronic inflammatory bowel disease is associated with the down-regulation of pro-inflammatory cytokines in lamina propria mononuclear cells. Clin Exp Immunol 140:417–426. doi: 10.1111/j.1365-2249.2005.02790.x Google Scholar
  6. 6.
    Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer cell 15:103–113. doi: 10.1016/j.ccr.2009.01.001 PubMedCrossRefGoogle Scholar
  7. 7.
    Waldner MJ, Neurath MF (2009) Novel cytokine-targeted therapies and intestinal inflammation. Curr Opin Pharmacol 9:702–707. doi: 10.1016/j.coph.2009.07.005 PubMedCrossRefGoogle Scholar
  8. 8.
    Iansante V, Capece D, Murgo S, Mancarelli M, Zazzeroni F, Alesse E (2009) Biotechnological approaches for the treatment of inflammatory diseases. Anti-Inflamm Anti-Allergy Agents Med Chem 8:51–71CrossRefGoogle Scholar
  9. 9.
    Van De Walle J, Hendrickx A, Romier B, Larondelle Y, Schneider YJ (2010) Inflammatory parameters in Caco-2 cells: effect of stimuli nature, concentration, combination and cell differentiation. Toxicol In Vitro 24:1441–1449. doi: 10.1016/j.tiv.2010.04.002 CrossRefGoogle Scholar
  10. 10.
    Garcıa-Domenech R, Gálvez J, de Julián-Ortiz JV, Pogliani L (2008) Some new trends in chemical graph theory. Chem Rev 108:1127–1169. doi: 10.1021/cr0780006 PubMedCrossRefGoogle Scholar
  11. 11.
    Kier LB, Hall LH (1986) Molecular connectivity in structure–activity analysis. Research Studies Press, Letchworth, HertfordshireGoogle Scholar
  12. 12.
    Kier LB, Hall LH (1976) Molecular connectivity in chemistry and drug research. Academic Press, New YorkGoogle Scholar
  13. 13.
    Amigó JM, Galvez J, Villar VM (2009) A review on molecular topology: applying graph theory to drug discovery and design. Naturwissenschaften 96:749–761. doi: 10.1007/s00114-009-0536-7 Google Scholar
  14. 14.
    Gálvez J, Gálvez-Llompart M, García-Domenech R (2012) Molecular topology as a novel approach for drug discovery. Expert Opin Drug Discov 7:133–153. doi: 10.1517/17460441.2012.652083 PubMedCrossRefGoogle Scholar
  15. 15.
    Bruno-Blanch L, Galvez J, Garcia-Domenech R (2003) Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity. Bioorg Med Chem Lett 13:2749–2754. doi: 10.1016/S0960-894X(03)00535-3 PubMedCrossRefGoogle Scholar
  16. 16.
    Garcia-Domenech R, Catala-Gregori A, Calabuig C, Anton-Fos G, Del Castillo L, Galvez J (2002) Predicting antifungal activity: a computational screening using topological descriptors. Internet Electron J Mol Des 1:339–350Google Scholar
  17. 17.
    Duart MJ, García-Domenech R, Gálvez J, Alemán PA, Martín-Algarra RV, Antón-Fos GM (2006) Application of a mathematical topological pattern of antihistaminic activity for the selection of new drug candidates and pharmacology assays. J Med Chem 49:3667–3673. doi: 10.1021/jm0580555 PubMedCrossRefGoogle Scholar
  18. 18.
    Rıos-Santamarina I, Garcıa-Domenech R, Gálvez J, Morcillo Esteban J, Santamarıa P, Cortijo J (2004) Getting new bronchodilator compounds from molecular topology. Eur J Pharm Sci 22:271–277. doi: 10.1016/j.ejps.2004.03.013 PubMedCrossRefGoogle Scholar
  19. 19.
    Gálvez J, Garcıa-Domenech R, Gomez-Lechon M, Castell J (2000) Use of molecular topology in the selection of new cytostatic drugs. J Mol Struct-THEOCHEM 504:241–248. doi: 10.1016/S0166-1280(00)00365-1 CrossRefGoogle Scholar
  20. 20.
    Antón-Fos G, Garcia-Domenech R, Perez-Gimenez F, Peris-Ribera J, Garcia-March F, Salabert-Salvador M (1994) Pharmacological studies of the two new hypoglycaemic compounds 4-(3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid and 1-(mesitylen-2-sulfonyl)-1H-1, 2, 4-triazole. Arzneim Forsch 44:821–826Google Scholar
  21. 21.
    Estrada E, Peña A, García-Domenech R (1998) Designing sedative/hypnotic compounds from a novel substructural graph-theoretical approach. J Comput Aided Mol Des 12: 583–595Google Scholar
  22. 22.
    Galvez-Llompart M, Zanni R, García-Domenech R (2011) Modeling natural anti-inflammatory compounds by molecular topology. Int J Mol Sci 12:9481–9503. doi: 10.3390/ijms12129481 PubMedCrossRefGoogle Scholar
  23. 23.
    Galvez-Llompart M, Giner RM, Recio MC, Candeletti S, Garcia-Domenech R (2010) Application of molecular topology to the search of novel NSAIDs: experimental validation of activity. Lett Drug Des Discov 7:438–445. doi: 10.2174/157018010791306597 Google Scholar
  24. 24.
    Mazier D, Mahmoudi N, Farhati K, Garcia-Domenech R, Galvez J, Derouin F, Danis M (2009) Monensin derivatives for preventing and treating plasmodium infections. PCT Int Appl WO 2009074649 A1 20090618Google Scholar
  25. 25.
    Llompart J, Galvez J, Pal K (2006) Treatment of cancer with MT477 derivatives (2006) US Patent Appl Publ US 20060014770 A1 20060119Google Scholar
  26. 26.
    Llompart J, Galvez J (2004) N,N-dicyclohexyl-(1S)-isoborneol-10-sulfonamide MT103 family members as antitumor and other therapeutic agents and corresponding treatments and compositions. US Patent Appl Publ US 20040059000 A1 20040325Google Scholar
  27. 27.
    Galvez J, Llompart J, Land D, Pasinetti G (2009) Mount Sinai School of Medicine of New York University, USA, Inc Medisyn Technologies, editors. Patent Application Country: Application: WO; WO; Priority Application Country: US patent WO2010114636. 2010 1007; Patent Application Date: 20100405; Priority Application Date: 20090403Google Scholar
  28. 28.
    Galvez J, Villar VM, Galvez-Llompart M, Amigo JM (2011) Chemistry explained by topology: an alternative approach. Comb Chem High Throughput Screen 14:279–283. doi: 10.2174/138620711795222464 PubMedCrossRefGoogle Scholar
  29. 29.
    Yamaguchi K, Yada M, Tsuji T, Hatanaka Y, Goda K, Kobori T (1999) 4-Phenylthiazole derivatives inhibit IL-6 secretion in osteoblastic cells and suppress bone weight loss in ovariectomized mice. Bioorg Med Chem Lett 9:957–960. doi: 10.1016/S0960-894X(99)00122-5 PubMedCrossRefGoogle Scholar
  30. 30.
    Lee SW, Kim MS, Park MH, Park SJ, Lee WS, Chang JS, Rho MC (2010) Alkamides from Piper longum and Piper nigrum as inhibitors of IL-6 action. Bull Korean Chem Soc 31:921–924. doi: 10.5012/bkcs.2010.31.04.921 CrossRefGoogle Scholar
  31. 31.
    Liu X, Wang J (2011) Anti-inflammatory effects of iridoid glycosides fraction of Folium syringae leaves on TNBS-induced colitis in rats. J Ethnopharmacol 133:780–787. doi: 10.1016/j.jep.2010.11.010 PubMedCrossRefGoogle Scholar
  32. 32.
    Tang JS, Zhao F, Gao H, Dai Y, Yao ZH, Hong K, Li J, Ye WC, Yao XS (2010) Characterization and online detection of surfactin isomers based on HPLC-MSn analyses and their inhibitory effects on the overproduction of nitric oxide and the release of TNF-\(\alpha \) and IL-6 in LPS-induced macrophages. Marine drugs 8:2605–2618. doi:  10.3390/md8102605 PubMedCrossRefGoogle Scholar
  33. 33.
    Guh JH, Chang WL, Yang J, Lee SL, Wei S, Wang D, Kulp SK, Chen CS (2010) Development of novel adenosine monophosphate-activated protein kinase activators. J Med Chem 53:2552–2561. doi: 10.1021/jm901773d PubMedCrossRefGoogle Scholar
  34. 34.
    Kuramoto M, Hayashi K, Yamaguchi K, Yada M, Tsuji T, Uemura D (1998) Structure–activity relationship of norzoanthamine exhibiting significant inhibition of osteoporosis. Bull Chem Soc Jpn 71:771–779CrossRefGoogle Scholar
  35. 35.
    Kagechika H, Kawachi E, Fukasawa H, Saito G, Iwanami N, Umemiya H, Hashimoto Y, Shudo K (1997) Inhibition of IL-1-induced IL-6 production by synthetic retinoids. Biochem Biophys Res Commun 231:243–248. doi: 10.1006/bbrc.1997.6087 PubMedCrossRefGoogle Scholar
  36. 36.
    Koch E, Klaas CA, Rüngeler P, Castro V, Mora G, Vichnewski W, Merfort I (2001) Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-[kappa] B. Biochem Pharmacol 62:795–801. doi: 10.1016/S0006-2952(01)00714-6 PubMedCrossRefGoogle Scholar
  37. 37.
    Enomoto A, Rho MC, Komiyama K, Hayashi M (2004) Inhibitory effects of bufadienolides on interleukin-6 in MH-60 cells. J Nat Prod 67:2070–2072. doi: 10.1021/np049950e PubMedCrossRefGoogle Scholar
  38. 38.
    Kahlon DK, Lansdell TA, Fisk JS, Tepe JJ (2009) Structural–activity relationship study of highly-functionalized imidazolines as potent inhibitors of nuclear transcription factor-[kappa] B mediated IL-6 production. Bioorg Med Chem 17:3093–3103. doi: 10.1016/j.bmc.2009.03.002 PubMedCrossRefGoogle Scholar
  39. 39.
    Enomoto A, Rho MC, Fukami A, Hiraku O, Komiyama K, Hayashi M (2004) Suppression of cancer cachexia by 20S, 21-epoxy-resibufogenin-3-acetate-a novel nonpeptide IL-6 receptor antagonist. Biochem Biophys Res Commun 323:1096–1102. doi: 10.1016/j.bbrc.2004.08.196 PubMedCrossRefGoogle Scholar
  40. 40.
    Bandgar BP, Patil SA, Totre JV, Korbad VL, Gacche RN, Hote BS, Jalde SS, Chavan HV (2010) Synthesis and biological evaluation of nitrogen-containing benzophenone analogues as TNF-[alpha] and IL-6 inhibitors with antioxidant activity. Bioorg Med Chem Lett 20:2292–2296. doi: 10.1016/j.bmcl.2010.02.001 PubMedCrossRefGoogle Scholar
  41. 41.
    Bharate SB, Mahajan TR, Gole YR, Nambiar M, Matan T, Kulkarni-Almeida A, Balachandran S, Junjappa H, Balakrishnan A, Vishwakarma RA (2008) Synthesis and evaluation of pyrazolo [3,4-b] pyridines and its structural analogues as TNF-\(\alpha \) and IL-6 inhibitors. Bioorg Med Chem 16:7167–7176. doi:  10.1016/j.bmc.2008.06.042 PubMedCrossRefGoogle Scholar
  42. 42.
    OTAVA Ltd. http://www.otavachemicals.com/. Accessed 6 April 2012
  43. 43.
    MicroSource Pure Natural Products Collection. http://www.msdiscovery.com/home.html. Accessed 14 Dec 2012
  44. 44.
    ChemDraw Ultra package (version 10.0). CambridgeSoft (2009)Google Scholar
  45. 45.
    Todeschini R, Consonni V (2008) Handbook of molecular descriptors. Wiley-VCH Verlag GmbH, Weinheim. doi: 10.1002/9783527613106.oth2 Google Scholar
  46. 46.
    StatSoft I (2009) STATISTICA (data analysis software system), version 9. Tulsa, USAGoogle Scholar
  47. 47.
    De Maesschalck R, Jouan-Rimbaud D, Massart D (2000) The mahalanobis distance. Chemom Intell Lab Syst 50:1–18. doi: 10.1016/S0169-7439(99)00047-7 CrossRefGoogle Scholar
  48. 48.
    Klecka WR (1980) Discriminant analysis. Sage Publications, Inc., Thousand OaksGoogle Scholar
  49. 49.
    Furnival GM (1971) All possible regressions with less computation. Technometrics 13:403–408CrossRefGoogle Scholar
  50. 50.
    Matthews BW (1975) Comparison of the predicted and observed secondary structure of T4 phage lysozyme. Biochim Biophys Acta 405:442–451PubMedCrossRefGoogle Scholar
  51. 51.
    McClish DK (1989) Analyzing a portion of the ROC curve. Med Decis Mak 9:190–195. doi: 10.1177/0272989X8900900307 CrossRefGoogle Scholar
  52. 52.
    Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172. doi: 10.1002/sim.2929 PubMedCrossRefGoogle Scholar
  53. 53.
    Gálvez J, García-Domenech R, de Gregorio Alapont C, de Julián-Ortiz J, Popa L (1996) Pharmacological distribution diagrams: a tool for de novo drug design. J Mol Graph 14:272–276. doi: 10.1016/S0263-7855(96)00081-1 PubMedCrossRefGoogle Scholar
  54. 54.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi: 10.1016/0022-1759(83)90303-4
  55. 55.
    Estrada E (1996) Spectral moments of the edge adjacency matrix in molecular graphs. 1. Definition and applications to the prediction of physical properties of alkanes. J Chem Inf Comput Sci 36:844–849. doi: 10.1021/ci950187r CrossRefGoogle Scholar
  56. 56.
    Cashman J, Burt H, Springate C, Gleave J, Jackson J (2004) Camptothecin-loaded films for the prevention of postsurgical adhesions. Inflammation Res 53:355–362. doi: 10.1007/s00011-004-1272-2 CrossRefGoogle Scholar
  57. 57.
    McLeod MJ (1980) Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S. Teratology 22:299–301PubMedCrossRefGoogle Scholar
  58. 58.
    El Alfy T, El Sawi S, Sleem A, Moawad D (2010) Investigation of flavonoidal content and biological activities of Chorisia insignis Hbk. leaves. Aust J Basic Appl Sci 4:1334–1348Google Scholar
  59. 59.
    Parish CR (1999) Fluorescent dyes for lymphocyte migration and proliferation studies. Immunol Cell Biol 77:499–508. doi: 10.1046/j.1440-1711.1999.00877.x PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang Y, Reenstra WW, Chidekel A (2001) Antibacterial activity of apical surface fluid from the human airway cell line Calu-3: pharmacologic alteration by corticosteroids and beta(2)-agonists. Am J Respir Cell Mol Biol 25:196–202PubMedCrossRefGoogle Scholar
  61. 61.
    Pelzer LE, Guardia T, Juarez AO, Guerreiro E (1998) Acute and chronic antiinflammatory effects of plant flavonoids. Il Farmaco 53:421–424. doi: 10.1016/S0014-827X(98)00046-9 PubMedCrossRefGoogle Scholar
  62. 62.
    Marante FJT, Castellano AG, Rosas FE, Aguiar JQ, Barrera JB (2003) Identification and quantitation of allelochemicals from the lichen Lethariella canariensis: phytotoxicity and antioxidative activity. J Chem Ecol 29:2049–2071CrossRefGoogle Scholar
  63. 63.
    Benavente-Garcia O, Castillo J (2008) Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 56:6185–6205. doi: 10.1021/jf8006568 PubMedCrossRefGoogle Scholar
  64. 64.
    Alencar N, Cavalcante C, Vasconcelos M, Leite K, Aragão K, Assreuy A, Nogueira N, Cavada B, Vale M (2005) Anti-inflammatory and antimicrobial effect of lectin from Lonchocarpus sericeus seeds in an experimental rat model of infectious peritonitis. J Pharm Pharmacol 57:919–922. doi: 10.1211/0022357056352 PubMedCrossRefGoogle Scholar
  65. 65.
    Shen MY, Liu YJ, Don MJ, Liu HY, Chen ZW, Mettling C, Corbeau P, Chiang CK, Jang YS, Li TH (2011) Combined phytochemistry and chemotaxis assays for identification and mechanistic analysis of anti-inflammatory phytochemicals in Fallopia japonica. PLoS ONE 6:e27480. doi: 10.1371/journal.pone.0027480
  66. 66.
    Mishchenko N, Fedoreev S, Bryukhanov V, Zverev YF, Lampatov V, Azarova O, Shkryl’ YN, Chernoded G (2007) Chemical composition and pharmacological activity of anthraquinones from Rubia cordifolia cell culture. Pharm Chem J 41:605–609. doi: 0091-150X/07/4111-0605 Google Scholar
  67. 67.
    Miller JW, Shukitt-Hale B, Villalobos-Molina R, Nadeau MR, Selhub J, Joseph JA (1997) Effect of l-Dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats. Clin Neuropharmacol 20:55–66Google Scholar
  68. 68.
    Su P, Wang G, Wu D, Sheng X (2008) Progress in rosmarinic acid biological activities and its sources. Shipin Yu Fajiao Gongye 34:135–138Google Scholar
  69. 69.
    Yoon IS, Au Q, Barber JR, Ng SC, Zhang B (2010) Development of a high-throughput screening assay for cytoprotective agents in rotenone-induced cell death. Anal Biochem 407:205–210. doi: 10.1016/j.ab.2010.08.011 PubMedCrossRefGoogle Scholar
  70. 70.
    Li J, Huang W, Zhang H, Wang X, Zhou H (2007) Synthesis of andrographolide derivatives and their TNF-[alpha] and IL-6 expression inhibitory activities. Bioorg Med Chem Lett 17:6891–6894. doi: 10.1016/j.bmcl.2007.10.009 PubMedCrossRefGoogle Scholar
  71. 71.
    Marquez-Martin A, Puerta RDL, Fernandez-Arche A, Ruiz-Gutierrez V, Yaqoob P (2006) Modulation of cytokine secretion by pentacyclic triterpenes from olive pomace oil in human mononuclear cells. Cytokine 36:211–217. doi: 10.1016/j.cyto.2006.12.007 PubMedCrossRefGoogle Scholar
  72. 72.
    Papi C, Aratari A, Moretti A, Mangone M, Margagnoni G, Koch M, Capurso L (2010) Oral beclomethasone dipropionate as an alternative to systemic steroids in mild to moderate ulcerative colitis not responding to aminosalicylates. Digest Dis Sci 55:2002–2007. doi: 10.1007/s10620-009-0962-6 PubMedCrossRefGoogle Scholar
  73. 73.
    Keller R (2004) Potential use of budesonide in inflammatory bowel diseases: extended ulcerative colitis. Topical steroids in gastroenterology and hepatology. In: Proceedings of the Falk Workshop—new findings on pathogenesis and progress in management of inflammatory bowel diseases, Part III. Berlin, Germany, June 14, 2003, pp 39–46Google Scholar
  74. 74.
    Kang B-S, Chung E-Y, Yun Y-P, Lee MK, Lee YR, Lee K-S, Min KR, Kim Y (2001) Inhibitory eEffects of anti-inflammatory drugs on interleukin-6 bioactivity. Biol Pharm Bull 24:701–703. doi: 10.1248/bpb.24.701 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • María Galvez-Llompart
    • 1
  • María del Carmen Recio Iglesias
    • 2
  • Jorge Gálvez
    • 1
  • Ramón García-Domenech
    • 1
  1. 1.Molecular Connectivity & Drug Design Research Unit, Department of Physical Chemistry, Faculty of PharmacyUniversity of ValenciaValenciaSpain
  2. 2.Department of Pharmacology, Faculty of PharmacyUniversity of ValenciaValenciaSpain

Personalised recommendations