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 ABC  Vol.6 No.5 , October 2016
Coumarin and Biscoumarin Inhibit in Vitro Obesity Model
Abstract: Coumarin, sulphonated coumarin, and biscoumarin compounds were examined for their effects on suppressing the adipocyte differentiation in 3T3-L1 cells. Many of them inhibited the adipocyte differentiation in a dose dependent manner, amongst them compounds (7), (28), and (33) significantly suppressed the adipogenic differenti-ation, and also exhibited lipolytic effect on mature adipocytes. The active compounds potentially imitate the AMP-activated protein kinase (AMPK) ligands, there- fore, binding of these compounds with AMPK possibly shuts down the anabolic pathways. Furthermore, these compounds were docked into binding pockets with reasonable pre-dicted binding constants in the low micromolar range. These results indicate that compounds (7), (28), and (33) inhibit adipogenic development in pre- adipocytes, having lipolytic effect on mature adipocytes, and can be potent activators of human AMPK.
Cite this paper: Mukhtar, F. , Stieglitz, K. , Ali, S. , Ejaz, A. , Choudhary, M. , Fakhri, M. , Salar, U. , Khan, K. (2016) Coumarin and Biscoumarin Inhibit in Vitro Obesity Model. Advances in Biological Chemistry, 6, 152-168. doi: 10.4236/abc.2016.65014.
References

[1]   Carmeliet, P. (2005) Angiogenesis in Life, Disease and Medicine. Nature, 438, 932-936.
https://doi.org/10.1038/nature04478

[2]   Dvorak, H.F. (2005) Angiogenesis: Update 2005. Journal of Thrombosis and Haemostasis, 3, 1835-1842.
https://doi.org/10.1111/j.1538-7836.2005.01361.x

[3]   Ferrara, N. and Kerbel, R.S. (2005) Angiogenesis as a Therapeutic Target. Nature, 438, 967- 974.
https://doi.org/10.1038/nature04483

[4]   Waki, H. and Tontonoz, P. (2007) Endocrine Functions of Adipose Tissue. Annual Review of Pathology, 2, 31-56.
https://doi.org/10.1146/annurev.pathol.2.010506.091859

[5]   Rayalam, S., Cella-Fera, M.A. and Baile, C.A. (2008) Phytochemicals and Regulation of the Adipocyte Life Cycle. Journal of Nutritional Biochemistry, 19, 717-726.
https://doi.org/10.1016/j.jnutbio.2007.12.007

[6]   Heal, D.J., Gosden, J. and Smith, S.L. (2009) Regulatory Challenges for New Drugs to Treat Obesity and Comorbid Metabolic Disorders. British Journal of Clinical Pharmacology, 68, 861-874.
https://doi.org/10.1111/j.1365-2125.2009.03549.x

[7]   Rodgers, R.J., Tschop, M.H. and Wilding, P.H. (2012) Anti-Obesity Drugs: Past, Present and Future. Disease Models & Mechanisms, 5, 621-626.
https://doi.org/10.1242/dmm.009621

[8]   Bray, G.E. and Frank, L.G. (1999) Current and Potential Drugs for Treatment of Obesity. Endocrine Reviews, 20, 805-875.
https://doi.org/10.1210/edrv.20.6.0383

[9]   Peng, X.M., Damu, G.L.V. and Zhou, C.H. (2013) Current Developments of Coumarin Compounds in Medicinal Chemistry. Current Pharmaceutical Design, 19, 3884-3930.
https://doi.org/10.2174/1381612811319210013

[10]   Salar, U., Khan, K.M., Jabeen, A., Faheem, A., Fakhri, M.I., Saad, S.M., Perveen, S. and Taha, M. (2016) Coumarin Sulfonates: As Potential Leads for ROS Inhibition. Bioorganic Chemistry, 69, 37-47.
https://doi.org/10.1016/j.bioorg.2016.09.006

[11]   Salar, U., Taha, M., Khan, K.M., Ismail, N.H., Imran, S., Perveen, S., Gul, S. and Wadood, A. (2016) Syntheses of New 3-Thiazolylcoumarin Derivatives, in Vitro α-Glucosidase Inhibitory Activity, and Molecular Modeling Studies. European Journal of Medicinal Chemistry, 122, 196-204.
https://doi.org/10.1016/j.ejmech.2016.06.037

[12]   Khan, K.M., Fakhri, M.I., Shaikh, N.N., Saad, S.M., Hussain, S., Perveen, S. and Choudhary, M.I. (2014) β-Glucuronidase Inhibitory Studies on Coumarin Derivatives. Medicinal Chemistry, 10, 778-782.
https://doi.org/10.2174/1573406410666140311093352

[13]   Gomez-Outes, A., Suarez-Gea, M.L., Calvo-Rojas, G., Lecumberri, R., Rocha, E., Pozo-Hernandez, C., Terleira-Fernandez, A.I. and Vargas-Castrillon, E. (2012) Discovery of Anticoagulant Drugs: A Historical Perspective. Current Drug Discovery Technologies, 9, 83- 104.
https://doi.org/10.2174/1570163811209020083

[14]   Anand, P., Singh, B. and Singh, N. (2012) A Review on Coumarins as Acetylcholineesterase Inhibitors for Alzheimer’s Disease. Bioorganic & Medicinal Chemistry, 20, 1175-1180.
https://doi.org/10.1016/j.bmc.2011.12.042

[15]   Kostova, I., Bhatia, S., Grigorov, P., Balkansky, S.S., Parmar, V.K., Prasad, A. and Saso, L. (2011) Coumarins as Antioxidants. Current Medicinal Chemistry, 18, 3929-3951.
https://doi.org/10.2174/092986711803414395

[16]   Riveiro, M.E., Kimpe, N.D. and Moglioni, A., Vazquez, R., Monczor, F., Shayo, C. and Da vio, C. (2010) Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives. Current Medicinal Chemistry, 17, 1325-1338.
https://doi.org/10.2174/092986710790936284

[17]   Wu, L., Wang, X., Xu, W., Farzaneh, F. and Xu, R. (2009) The Structure and Pharmacological Functions of Coumarins and Their Derivatives. Current Medicinal Chemistry, 16, 4236-4260.
https://doi.org/10.2174/092986709789578187

[18]   Cravotto, G., Nano, G.M., Palmisano, S.G. and Tagliapietra, S. (2003) The Chemistry of Coumarin Derivatives, Part XIII. The Reactivity of 4-Hydroxycoumarin under Heterogenous High Intensity Sonochemical Conditions. Synthesis, 8, 1286-1291.

[19]   Attaur-Rahman, Shabbir, M., Ziauddin, S.S., Jabar, A. and Choudhary, M.I. (1997) Cinnamates and Coumarins from the Leaves of Murraya paniculata. Phytochemistry, 44, 683-685.
https://doi.org/10.1016/S0031-9422(96)00617-6

[20]   Al-Amiery, A.A., Al-Bayati, R.I.H., Saour, K.Y. and Radi, M.F. (2012) Cytotoxicity, Anti-oxidant, and Antimicrobial Activities of Novel 2-Quinolone Derivatives Derived from Coumarin. Research on Chemical Intermediates, 38, 559-569.
https://doi.org/10.1007/s11164-011-0371-2

[21]   Kontoggiorgis, C. and Hadjipavolou-Litiana, D. (2003) Biological Evaluation of Several Derivatives Desined Possible Anti-Inflammatory/Antioxidant Agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 18, 63-69.
https://doi.org/10.1080/1475636031000069291

[22]   Smyth, T., Ramachandran, V.N. and Smyth, W.F. (2009) A Study of Antimicrobial Activity of Naturally Occurring and Synthetic Coumarins. International Journal of Antimicrobial Agents, 33, 421-426.
https://doi.org/10.1016/j.ijantimicag.2008.10.022

[23]   Liu, W., Hua, J., Zhou, J., Zhang, H., Zhu, H., Cheng, Y. and Gust, R. (2012) Synthesis and in Vitro Antitumor Activity of Novel Scopoletin Derivatives. Bioorganic & Medicinal Chemistry Letters, 22, 5008-5012.
https://doi.org/10.1016/j.bmcl.2012.06.014

[24]   Iranshahi, M., Askari, M., Sahebkar, A. and Hadjipavlou-Litiana, D. (2009) Evaluation of Antioxidant, Anti-Inflammatory and Lipoxygenase Inhibitory Activities of the Prenylated Coumarin Umbelliprenin. DARU Journal of Pharmaceutical Sciences, 17, 99-103.

[25]   Borges, F., Roleira, F., Milhazes, N., Santana, L. and Uriarte, E. (2005) Simple Coumarins and Analogues in Medicinal Chemistry: Occurrence, Synthesis and Biological Activity. Current Medicinal Chemistry, 12, 887-916.
https://doi.org/10.2174/0929867053507315

[26]   Manolov, I. and Danchev, N. (2003) Synthesis and Pharmacological Investigations of Some 4-Hydroxycoumarin Derivatives. Archiv der Pharmazie, 336, 83-94.
https://doi.org/10.1002/ardp.200390010

[27]   Jung, J.C. and Park, O.S. (2009) Synthetic Approaches and Biological Activities of 4-Hydroxycoumarin Derivatives. Molecules, 14, 4790-4803.
https://doi.org/10.3390/molecules14114790

[28]   Manolov, I., Maichle-Moessmer, C. and Dancher, N. (2006) Synthesis, Structure, Toxicological and Pharmacological Investigations of 4-Hydroxycoumarin Derivatives. European Journal of Medicinal Chemistry, 41, 882-890.
https://doi.org/10.1016/j.ejmech.2006.03.007

[29]   Su, C.X., Mouscadet, J.F., Chiang, C.C., Tsai, H.J. and Hsu, L.Y. (2006) HIV-1 Integrase Inhibition of Biscoumarin Analogues. Chemical and Pharmaceutical Bulletin, 54, 682-686.
https://doi.org/10.1248/cpb.54.682

[30]   Zhao, H., Namati, N., Hong, H., Mazumder, A., Shaomeng, W., Sanjay, S., George, W.A.M., Yves, P. and Terrence, R.B. (1997) Coumarin-Based Inhibitors of HIV-Integrase. Journal of Medicinal Chemistry, 40, 242-249.
https://doi.org/10.1021/jm960450v

[31]   Nolan, K.A., Zhao, H., Faulder, P.F., Frenkel, A.D., Timson, J.D., Siegel, D., Ross, D., Burke Jr., T.R., Stratford, I.J. and Bryce, A.R. (2007) Coumarin-Based Inhibitors of Human NAD(P)H: Quinone Oxidoreductase-1. Identification, Structure-Activity, Off-Target Effects and in Vitro Human Pancreatic Cancer Toxicity. Journal of Medicinal Chemistry, 50, 6316-6325.
https://doi.org/10.1021/jm070472p

[32]   Hamdi, N., Puetra, M.C. and Valerga, P. (2008) Synthesis, Structure, Antimicrobial and Antioxidant Investigations of Dicoumarol and Related Compounds. European Journal of Medicinal Chemistry, 43, 2541-2548.
https://doi.org/10.1016/j.ejmech.2008.03.038

[33]   Khan, K.M., Iqbal, S., Lodhi, M.A., Maharvi, G.M., Zia-Ullah, Choudhary, M.I., Attaur-Rahman and Perveen, S. (2004) Biscoumarin: New Class of Urease Inhibitors, Economical Synthesis and Activity. Bioorganic & Medicinal Chemistry, 12, 1963-1968.
https://doi.org/10.1016/j.bmc.2004.01.010

[34]   Choudhary, M.I., Fatima, N., Khan, K.M., Jalil, S., Iqbal, S. and Attaur-Rahman (2006) New Biscoumarin Derivatives-Cytotoxicity and Enzyme Inhibitory Activities. Bioorganic & Medicinal Chemistry, 14, 8066-8072.
https://doi.org/10.1016/j.bmc.2006.07.037

[35]   Kostova, I., Momekov, G., Zaharieva, M. and Karaivanova, M. (2005) Cytotoxic Activity of New Lanthanum (III) Complexes of Bis-Coumarins. European Journal of Medicinal Chemistry, 40, 542-551.
https://doi.org/10.1016/j.ejmech.2004.12.007

[36]   Tabatabaeian, K., Heidari, H., Khorshidi, A., Ghani, M.M. and Mahmoodi, N.O. (2012) Synthesis of Biscoumarin Derivatives by the Reaction of Aldehydes and 4-Hydroxycoumarin Using Ruthenium (III) Chloride Hydrate as a Versatile Homogenous Catalyst. Journal of the Serbian Chemical Society, 77, 407-413.
https://doi.org/10.2298/JSC110427189T

[37]   Ejaz, A., Wu, D., Kwan, P. and Meydani, M. (2009) Curcumin Inhibits Adipogenesis in 3T3-L1 Adipocytes and Angiogenesis and Obesity in C57/BL Mice. Journal of Nutrition, 139, 919-925.
https://doi.org/10.3945/jn.108.100966

[38]   Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S. and Olson, A.J. (2009) Autodock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry, 16, 2785-2791.
https://doi.org/10.1002/jcc.21256

[39]   Xiao, B., Sanders, M.J., Underwood, E., Heath, R., Mayer, F., Carmena, D., Jing, C., Walker, P.A., Eccleston, J.F., Haire, L.F., Saiu, P., Howell, S.A., Aasland, R., Martin, S.R., Carling, D. and Gamblin, S.J. (2011) Structure of Mammalian Ampk and Its Regulation by Adp. Nature, 472, 230.
https://doi.org/10.1038/nature09932

[40]   Xiao, B., Sanders, M.J., Carmena, D., Bright, N.J., Haire, L.F., Underwood, E., Patel, B.R., Heath, R.B., Walker, P.A., Hallen, S., Giordanetto, F., Martin, S.R., Carling, D. and Gamblin, S.J. (2013) Structural Basis of Ampk Regulation by Small Molecule Activators. Nature Communications, 4, 3017.
https://doi.org/10.1038/ncomms4017

 
 
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