Molecular Docking of 4-Tert-buthyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) on Fas Receptor (CD95)

Oscar Zuñiga, Víctor H. Vázquez, Ana María Velázquez, Víctor H. Abrego, Sandra Díaz-Barriga Arceo, Patricia Ramírez, Roberto Díaz, Enrique Angeles

Laboratorio de Química Medicinal Departamento de Ciencias Químicas Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, México.
Laboratorio de Toxicología y Genética, Departamento de C. Biológicas, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Cuautitlán Izcalli, México.

DOI: 10.4236/jct.2013.41026                

Abstract

The balance between cell proliferation and cell growth characterizes tissue homeostasis on one side and cell death on the other side. Fas receptor-mediated apoptosis is a control mechanism for tissue homeostasis, and avoiding this death pathway predisposes to many human diseases, including cancer. Current therapies for this disease are invasive and do not have the desired effect in the control of the disease. In this context, the search for new drugs that contribute to a better treatment is gaining more relevance. 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol (LQM319) [1,2] is a drug currently in preclinical stage, and we have shown that it has a hypertensive effect, similar to captopril, in a hypertensive rat model. Different studies have shown that some chemicals that are used as antihypertensive agents have an antineoplastic effect against certain types of cancer, as is the case of hydralazine [3], and captopril [4], among others [5]. On the other hand, it has been reported that morpholine derivatives may activate Fas (CD95)-mediated apoptosis. The aim of the present study was to show the interaction between CD95 (receptor) and thiomorpholine derivatives (ligand) using molecular modeling and docking studies, and to elucidate the possible action mechanism of 4-tert-butyl-bis-(2,6-thiomorpholin-4-ylmethyl)-1-phenol.

Keywords

Fas Receptor (CD95); Fas Ligand (FasL); Docking

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	A. Velázquez, L. Martínez, V. Abrego, M. A. Balboa, L. A. Torres, B. Camacho, S. Díaz-Barriga, A. Romero, R. López-Casta?ares and E. Angeles, “Synthesis and Antihypertensive Effects of New Methylthiomorpholinphenol Derivatives,” European Journal of Medicinal Chemistry, Vol.43, No. 3, 2008, pp. 486-500. doi:10.1016/j.ejmech.2007.04.003
[2]	A. Ma. Velázquez, G. Díaz, A. Ramírez, R. Hernández, H. Santillán L. Martínez, V. Abrego, M.A. Balboa, L.A. Torres, B. Camacho, S. Díaz-Barriga, A. Romero, R. López-Casta?ares, A. Due?as-González, G. Cabrera and E. Angeles, “A Novel One Pot, Solvent-Free Mannich Synthesis of Methylpiperidinyl Phenols, Methylphenylmorpholinyl Phenols and Methylthiophenylmorpholinyl Phenols Using Infrared Light Irradiation,” Arkivoc, Vol. ii, No. 2006, pp. 150-161.
[3]	E. Angeles, V. H. Vázquez, O. Vázquez, A. Ma. Velázquez, A. Ramírez, L. Martínez, S. Díaz-Barriga, A. Romero, G. Cabrera, R. López-Casta?ares and A. Due?as, “Computational Studies of 1-Hydrazinophthalazine (Hydralazine) as an Antineoplasic Agent. Docking Studies on Methyltransferase,” Letters in Drug Design and Discovery, Vol. 2, No. 4, 2005, pp. 282-286. doi:10.2174/1570180054038413
[4]	K. Hudson and G. Ronquist, “Medical Use of Captopril for the Treatment and Prophylaxis of Cancer,” Patent No.WO2003077909, 2003.
[5]	Y. K. Chae, M. E. Valsecchi, J. Kim, A. L. Bianchi, D. Khemasuwan, A. Desai and W. Tester, “Therapeutic Combination and Methods of Treatment with a dll4 Antagonist and an Anti-Hypertensive Agent,” Cancer Investigation, Vol. 29, No. 9, 2011, pp. 585-593. doi:10.3109/07357907.2011.616252
[6]	D. Kültz, “Molecular and Evolutionary Basis of the Cellular Stress Response,” Annual Review of Physiology, Vol. 67, 2005, pp. 225-257. doi:10.1146/annurev.physiol.67.040403.103635
[7]	S. Fulda and K. M. Debatin, “Extrinsic versus Intrinsic Apoptosis Pathways in Anticancer Chemotherapy,” Oncogene, Vol. 25, No. 34, 2006, pp. 4798-4811. doi:10.1038/sj.onc.1209608
[8]	V. Zuzarte-Luis and J. M. Hurle, “Programmed Cell Death in the Developing Limb,” The International Journal of Developmental Biology, Vol. 6, No. 7, 2002, pp. 871-876.
[9]	P. Meier, A. Finch and G. Evan, “Apoptosis in Development,” Nature, Vol. 407, No. 6805, 2000, pp. 796-801. doi:10.1038/35037734
[10]	M. Raff, “Cell Suicide for Beginners,” Nature, Vol. 396, No. 6707, 1998, pp.119-122. doi:10.1038/24055
[11]	P. Krammer, “CD95’s Deadly Mission in the Immune System,” Nature, Vol. 407, No. 6805, 2000, pp. 789-795. doi:10.1038/35037728
[12]	A. Saraste and K. Pulkki, “Morphologic and Biochemical Hallmarks of Apoptosis,” Cardiovascular Research, Vol. 45, No. 3, 2000, pp. 528-37. doi:10.1016/S0008-6363(99)00384-3
[13]	U. Sartorius, I. Schmitz and P. Krammer, “Molecular Mechanisms of Death-Receptor-Mediated Apoptosis,” ChemBioChem, Vol. 2, No. 1, 2001, pp. 20-29. doi:10.1002/1439-7633(20010105)2:1<20::AID-CBIC20>3.0.CO;2-X
[14]	M. Lenardo, K. Chan, F. Hornung, H. McFarland, R. Siegel, J. Wang and L. Zheng, “Mature T Lymphocyte Apoptosis: Immune Regulation in a Dynamic and Unpredictable Antigenic Environmental,” Annual Review of Immunology, Vol. 17, 1999, pp. 221-253. doi:10.1146/annurev.immunol.17.1.221
[15]	S. Nagata, “Fas Ligand-Induced Apoptosis,” Annual Review of Genetics, Vol. 33, 1999, pp. 29-55. doi:10.1146/annurev.genet.33.1.29
[16]	K. Bailey, H. Cook and C. McMaster, “The Phospholipid Scramblase PLSCR1 Increases UV Induced Apoptosis Primarily through the Augmentation of the Intrinsic Apoptotic Pathway and Independent of Direct Phosphorylation by Protein Kinase C δ,” Biochimica et Biophysica Acta, Vol. 1733, No. 2-3, 2005, pp. 199-209. doi:10.1016/j.bbalip.2004.12.013
[17]	J. J. Alam, “Apoptosis: Target for Novel Drugs,” Trends in Biotechnology, Vol. 21, No. 11, 2003, pp. 479-483. doi:10.1016/j.tibtech.2003.08.006
[18]	J. A. Folkes, K. Ahmadi, K. Alderton, S. Alix, J. S. Baker, G. Box, S. Chuckowree, A. Clarke, P. Depledge, A. S. Eccles, S. Friedman, A. Hayes, C. Hancox, A. Kugendradas, L. Lensun, P. Moore, G. A. Olivero, J. Pang, S. Patel, H. G. Pergl-Wilson, I. F. Raynaud, A. Robson, N. Saghir, L. Salphati, S. Sohal, M. H. Ultsch, M. Valenti, H. J. Wallweber, N. C. Wan and C. Wiesmann, “The Identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer,” Journal of Medicinal Chemistry, Vol. 51, No. 18, 2008, pp. 5522-5532. doi:10.1021/jm800295d
[19]	H. Qiuxia, Z. Xingshang, S. Mei, Z. Jing, Z. Shangli and M. Junying, “Novel Morpholin-3-One Derivatives Induced Apoptosis and Elevated the Level of P53 and Fas in A549 Lung Cancer Cells,” Bioorganic & Medicinal Chemistry, Vol. 15, No. 11, 2007, pp. 3889-3895. doi:10.1016/j.bmc.2007.03.008
[20]	M. Hayakawa, H. Kaizawa, H. Moritomo, T. Koizumi, T. Ohishi, M. Okada, S. Tsukamoto, P. Parker, P. Workman and M. Waterfield, “Synthesis and Biological Evaluation of 4-Morpholino-2-phenylquinazolines and Related Derivatives as Novel PI3 Kinase p110α Inhibitors,” Bioorganic & Medicinal Chemistry, Vol. 14, No. 20, 2006, pp. 6847-6858. doi:10.1016/j.bmc.2006.06.046
[21]	D. Yin, M. Woodruff, Y. Zhang, S Whaley, J. Miao, K. Ferslew, J. Zhao and C. Stuart, “Morphine Promotes Jurkat Cell Apoptosis through Pro-Apoptotic FADD/P53 and Anti-Apoptotic PI3K/Akt/NF-nB Pathways,” Journal of Neuroimmunology, Vol. 174, No. 1, 2006, pp. 101-107. doi:10.1016/j.jneuroim.2006.02.001
[22]	V. Dzau, A. J. Folkes, K. Ahmadi, W. K. Alderton, S. Alix, S. J. Baker, G. Box, I. S. Chuckowree, P. A. Clarke, P. Depledge, S. A. Eccles, L. S. Friedman, A. Hayes, T. C. Hancox, A. Kugendradas, L. Lensun, P. Moore, A. G. Olivero, J. Pang, S. Patel, G. H. Pergl-Wilson, F. I. Raynaud, A. Robson, N. Saghir, L. Salphati, S. Sohal, M. H. Ultsch, M. Valenti, H. J. Wallweber, N. C. Wan, C. Wiesmann, P. Workman, A. Zhyvoloup, M. J. Zvelebil and S. J. Shuttleworth. “The Identification of 2-(1H-Indazol-4-yl)-6-(4-Methanesulfonyh-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyperidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer,” Journal of Medicinal Chemistry, Vol. 51, No. 18, 1994, pp. 5522-5532.
[23]	R. Wang, A. Zagariya, E. Ang, O. Ibarra-Sunga and B. D. Uhal, “Fas-Induced Apoptosis of Alveolar Epithelial Cells Requires ANG. II II Generation and Receptor Interaction,” American Journal of Physiology. Lung Cellular and Molecular Physiology, Vol. 277, Pt. 1, 1999, pp. 1245-1250.
[24]	A. Molteni, W. Ward, C. Ts’ao, N. Solliday and M. Dunne, “Monocrotaline-Induced Pulmonary Fibrosis in Rats: Amelioration by Captopril and Penicillamine,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 180, No. 1, 1985, pp. 112-120.
[25]	H. J. Neo, I. E. Ager, W. P. Angus, J. Zhu, B. C. Herath and C. Christophi, “Changes in the Renin Angiotensin System during the Development of Colorectal Cancer Liver Metastases,” Cancer, Vol. 10, No. 134, 2010, pp. 1-11.