Geldanamycin (1) had been isolated as a major compound from Streptomyces zerumbet W14; an endophyte of Zingiber zerumbet (L.) Smith. Two new geldanamycin derivatives; 17-(tryptamine)-17-demethoxygeldanamycin (2) and 17-(5’-methoxytryptamine)-17-demethoxygeldanamycin (3) were synthe- sized and their anti-inflammatory activity was evaluated in LPS-induced macrophage RAW 264.7 cells by investigating their effects on the inhibition of production of NO, PGE 2 , TNF- α , IL-1 β , IL-6 and IL-10. The data obtained were consistent with the modulation of TNF-α, IL-1β, IL-6, IL-10 production by these derivatives at concentration of 1 to 5 μg/ml. A similar effect was also observed when LPS-induced NO release and PGE2 production were tested. The inhibitory effects were shown in concentration-dependent manners. From the obtained results, it was concluded that two new gelda- namycin derivatives possess anti-inflammatory activity on LPS-induced RAW 264.7 cells. They could be useful for the management of inflammatory diseases.
Li, Y.H., Tao, P.Z., Liu, Y.Z. and Jiang, J.D. (2004) Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 in Vitro. Antimicrobial Agents and Chemotherapy, 48, 867-872. https://doi.org/10.1128/aac.48.3.867-872.2004
Modi, S., Stopeck, A., Linden, H., Solit, D., Chandarlapaty, S., et al. (2011) HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab. Clinical Cancer Research, 17, 5132-5139. https://doi.org/10.1158/1078-0432.ccr-11-0072
Supko, J.G., Hickman, R.L., Grever, M.R. and Malspeis, L. (1995) Preclinical Pharmacologic Evaluation of Geldanamycin as an Antitumor Agent. Cancer Chemotherapy and Pharmacology, 36, 305-315. https://doi.org/10.1007/s002800050328
Kitson, R.R., Chang, C.H., Xiong, R., Williams, H.E., Davis, A.L., et al. (2013) Synthesis of 19-Substituted Geldanamycins with Altered Conformations and Their Binding to Heat Shock Protein Hsp90. Nature Chemistry, 5, 307-314 https://doi.org/10.1038/nchem.1596
Shan, G.Z., Peng, Z.G., Li, Y.H., Li, D., Li, Y.P., et al. (2011) A Novel Class of Geldanamycin Derivatives as HCV Replication Inhibitors Targeting on Hsp90: Synthesis, Structure-Activity Relationships and Anti-HCV Activity in GS4.3 Replicon Cells. Journal of Antibiotics, 64, 177-182.
Li, Y.P., Shan, G.Z., Peng, Z.G., Zhu, J.H., Meng, S., et al. (2010) Synthesis and Biological Evaluation of Heat Shock Protein 90 Inhibitors: Geldanamycin Derivatives with Broad Antiviral Activities. Antiviral Chemistry and Chemotherapy, 20, 259-268. https://doi.org/10.3851/imp1631
Lin, Z., Peng, R., Li, Z., Wang, Y., Lu, C., et al. (2015) 17-ABAG, a Novel Geldanamycin Derivative, Inhibits LNCaP-Cell Proliferation through Heat Shock Protein 90 Inhibition. International Journal of Molecular Medicine, 36, 424-432. https://doi.org/10.3892/ijmm.2015.2239
Tian, Z.Q., Liu, Y., Zhang, D., Wang, Z., Dong, S.D., et al. (2004) Synthesis and Biological Activities of Novel 17-Aminogeldanamycin Derivatives. Bioorganic and Medicinal Chemistry, 12, 5317-5329. https://doi.org/10.1016/j.bmc.2004.07.053
Wrona, I.E., Gozman, A., Taldone, T., Chiosis, G. and Panek, J.S. (2010) Synthesis of Reblastatin, Autolytimycin, and Non-Benzoquinone Analogues: Potent Inhibitors of Heat Shock Protein 90. Journal of Organic Chemistry, 75, 2820-2835. https://doi.org/10.1021/jo1000109
Taechowisan, T., Puckdee, W. and Phutdhawong, W.S. (2019) Streptomyces zerumbet, a Novel Species from Zingiber zerumbet (L.) Smith and Isolation of Its Bioactive Compounds. Advances in Microbiology, 9, 194-219. https://doi.org/10.4236/aim.2019.93015
Kousar, S., Anjuma, S.N., Jaleel, F., Khana, J. and Naseema, S. (2017) Biomedical Significance of Tryptamine: A Review. Journal of Pharmacovigilance, 5, 239. https://doi.org/10.4172/2329-6887.1000239
Pal, C., Bindu, S., Dey, S., Alam, A., Goyal, M., et al. (2012) Tryptamine-Gallic Acid Hybrid Prevents Non-Steroidal Anti-Inflammatory Drug-Induced Gastropathy: Correction of Mitochondrial Dysfunction and Inhibition of Apoptosis in Gastric Mucosal Cells. Journal of Biological Chemistry, 287, 3495-3509. https://doi.org/10.1074/jbc.m111.307199
Green, L.C., Wagner, D.A., Glogowski, J., Skipper, P.L., Wishnok, J.S., et al. (1982) Analysis of Nitrate, Nitrite, and [15N] Nitrate in Biological Fluids. Analytical Biochemistry, 126, 131-138. https://doi.org/10.1016/0003-2697(82)90118-x
ōmura, S., Nakagawa, A. and Sadakane, N. (1979) Structure of Herbimycin a New Ansamycin Antibiotic. Tetrahedron Letters, 20, 4323-4326. https://doi.org/10.1016/s0040-4039(01)86578-3
Qin, H.L. and Panek, J.S. (2008) Total Synthesis of the Hsp90 Inhibitor Geldanamycin. Organic Letters, 10, 2477-2479. https://doi.org/10.1021/ol800749w
Dunzendorfer, S., Lee, H.K., Soldau, K. and Tobias, P.S. (2004) TLR4 Is the Signaling but Not the Lipopolysaccharide Uptake Receptor. Journal of Immunology, 173, 1166-1170. https://doi.org/10.4049/jimmunol.173.2.1166
Ji, Y. and Qiang, W.G. (2010) Inhibition Effects of Valsartan on Cell Proliferation, Expression Inflammatory Factors and Reactive Oxygen Species Production of Macrophages. Journal of Shanghai Jiaotong University (Medical Science), 30, 292-295.
Coussens, L.M. and Werb, Z. (2002) Inflammation and Cancer. Nature, 420, 860-867. https://doi.org/10.1038/nature01322
Babior, B.M. (2000) Phagocytes and Oxidative Stress. American Journal of Medicine, 109, 33-44.
Closa, D. and Folch-Puy, E. (2004) Oxygen Free Radicals and the Systemic Inflammatory Response. International Union of Biochemistry and Molecular Biology Life, 56, 185-191. https://doi.org/10.1080/15216540410001701642
Hussain, S.P., Trivers, G.E., Hofseth, L.J., He, P., Shaikh, I., et al. (2004) Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis. Cancer Research, 64, 6849-6853. https://doi.org/10.1158/0008-5472.can-04-2201
Hodge, D.R., Hurt, E.M. and Farrar, W.L. (2005) The Role of IL-6 and STAT3 in Inflammation and Cancer. European Journal of Cancer, 41, 2502-2512. https://doi.org/10.1016/j.ejca.2005.08.016
Sarkar, D., Saha, P., Gamre, S., Bhattacharjee, S., Hariharan, C., et al. (2008) Anti-Inflammatory Effect of Allylpyrocatechol in LPS-Induced Macrophages Is Mediated by Suppression of iNOS and COX-2 via the NF-κB Pathway. International Immunopharmacology, 8, 1264-1271. https://doi.org/10.1016/j.intimp.2008.05.003
Guan, Q. and Zhang, J. (2017) Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease. Mediators of Inflammation, 2017, Article ID: 4810258. https://doi.org/10.1155/2017/4810258
Croft, M. and Siegel, R.M. (2017) Beyond TNF: TNF Superfamily Cytokines as Targets for the Treatment of Rheumatic Diseases. Nature Reviews Rheumatology, 13, 217-233. https://doi.org/10.1038/nrrheum.2017.22
Delgado, A.V., Mcmanus, A.T. and Chambers, J.P. (2003) Production of Tumor Necrosis Factor-Alpha, Interleukin 1-Beta, Interleukin 2, and Interleukin 6 by Rat Leukocyte Subpopulations after Exposure to Substance P. Neuropeptides, 37, 355-361. https://doi.org/10.1016/j.npep.2003.09.005
Palomo, J., Dietrich, D., Martin, P., Palmer, G. and Gabay, C. (2015) The Interleukin (IL)-1 Cytokine Family-Balance between Agonists and Antagonists in Inflammatory Diseases. Cytokine, 76, 25-37. https://doi.org/10.1016/j.cyto.2015.06.017
Alunno, A., Carubbi, F., Giacomelli, R. and Gerli, R. (2017) Cytokines in the Pathogenesis of Rheumatoid Arthritis: New Players and Therapeutic Targets. BMC Rheumatology, 1, 3. https://doi.org/10.1186/s41927-017-0001-8
Harden, L.M., Rummel, C., Laburn, H.P., Damm, J., Wiegand, F., et al. (2014) Critical Role for Peripherally-Derived Interleukin-10 in Mediating the Thermoregulatory Manifestations of Fever and Hypothermia in Severe Forms of Lipopolysaccha-ride-Induced Inflammation. Pflugers Archiv: European Journal of physiology, 466, 1451-1466. https://doi.org/10.1007/s00424-013-1371-4
LeMay, L.G., Vander, A.J. and Kluger, M.J. (1990) Role of Interleukin 6 in Fever in Rats. American Journal of Physiology, 258, 798-803. https://doi.org/10.1152/ajpregu.1990.258.3.R798
Watkins, L.R., Maier, S.F. and Goehler, L.E. (1995) Immune Activation: The Role of Proinflammatory Cytokines in Inflammation, Illness Responses and Pathological Pain States. Pain, 63, 289-302. https://doi.org/10.1016/0304-3959(95)00186-7
Masferrer, J.L., Zweifel, B.S., Manning, P.T., Hauser, S.D., Leahy, K.M., et al. (1994) Selective Inhibition of Inducible Cyclooxygenase 2 in Vivo Is Anti-Inflammatory and Nonulcerogenic. Proceedings of the National Academy of Sciences of the United States of America, 91, 3228-3232. https://doi.org/10.1073/pnas.91.8.3228
Laveti, D., Kumar, M., Hemalatha, R., Sistla, R., Naidu, V.G. et al. (2013) Anti-inflammatory Treatments for Chronic Diseases: A Review. Inflammation and Allergy Drug Targets, 12, 349-361. https://doi.org/10.2174/18715281113129990053
Monacada, S. and Higgs, A. (1993) The L-Arginine-Nitric Oxide Pathway. The New England Journal of Medicine, 329, 2002-2012. https://doi.org/10.1056/NEJM199312303292706
Roe, S., Prodromou, C., O’Brien, R., Ladbury, J., Piper, P., et al. (1999) Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin. Journal of Medicinal Chemistry, 42, 260-266. https://doi.org/10.1021/jm980403y
Ochel, H.J., Eichhorn, K. and Gademann, G. (2001) Geldanamycin, the Prototype of a Class of Antitumor Drugs Targeting the Heat Shock Protein 90 Family of Molecular Chaperones. Cell Stress and Chaperones, 6, 105-112.
Bucci, M., Roviezzo, F., Cicala, C., Sessa, W.C. and Cirino, G. (2000) Geldanamycin, an Inhibitor of Heat Shock Protein 90 (Hsp90) Mediated Signal Transduction Has Anti-Inflammatory Effects and Interacts with Glucocorticoid Receptor In Vivo. British Journal of Pharmacology, 131, 13-16. https://doi.org/10.1038/sj.bjp.0703549
Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., et al. (2000) Structure of TPR Domain-Peptide Complexes, Critical Elements in the Assembly of the Hsp70-Hsp90 Multichaperone Machine. Cell, 101, 199-210. https://doi.org/10.1016/S0092-8674(00)80830-2
Davis, M. and Carbott, D. (1999) Herbimycin A and Geldanamycin Inhibit Okadaic Acid-Induced Apoptosis and p38 Activation in NRK-52E Renal Epithelial Cells. Toxicology and Applied Pharmacology, 161, 59-74. https://doi.org/10.1006/taap.1999.8765
Bijlmakers, M.J. and Marsh, M. (2000) Hsp90 Is Essential for the Synthesis and Subsequent Membrane Association, but Not the Maintenance, of the Src-Kinase p56lck. Molecular Biology of the Cell, 11, 1499-1432. https://doi.org/10.1091/mbc.11.5.1585
Richter, K. and Buchner, J. (2001) Hsp90, Chaperoning Signal Transduction. Journal of Cellular Physiology, 188, 281-290. https://doi.org/10.1002/jcp.1131
Pritchard, K.A., Ackerman, A.W., Gross, E.R., Stepp, D.W., Shi, Y., et al. (2001) Heat Shock Protein 90 Mediates the Balance of Nitric Oxide and Superoxide Anion from Endothelial Nitric-Oxide Synthase. Journal of Biological Chemistry, 276, 17621-17624. https://doi.org/10.1074/jbc.C100084200
Marczin, N., Papapetropoulos, A. and Catravas, J.D. (1993) Tyrosine Kinase Inhibitors Suppress Endotoxin- and IL-1 Beta-Induced NO Synthesis in Aortic Smooth Muscle Cells. American Journal of Physiology, 265, 1014-1018. https://doi.org/10.1152/ajpheart.1993.265.3.H1014
Schulte, T.W., An, W.G. and Neckers, L.M. (1997) Geldanamycin-Induced Desta-Bilization of Raf-1 Involves the Proteasome. Biochemical and Biophysical Research Communications, 239, 655-659. https://doi.org/10.1006/bbrc.1997.7527
Pratt, W. (1998) The Hsp90-Based Chaperone System, Involvement in Signal Transduction from a Variety of Hormone and Growth Factor Receptors. Proceedings of the Society for Experimental Biology and Medicine, 217, 420-434. https://doi.org/10.3181/00379727-217-44252
Sakagami, M., Morrison, P. and Welch, W. (1999) Benzoquinoid Ansamycins (Herbimycin A and Geldanamycin) Interfere with the Maturation of Growth Factor Receptor Tyrosine Kinases. Cell Stress and Chaperones, 4, 19-28.
Schnaider, T., Somogyi, J., Csermely, P. and Szamel, M. (2000) The Hsp90-Specific Inhibitor Geldanamycin Selectively Disrupts Kinase-Mediated Signaling Events of T-Lymphocyte Activation. Cell Stress and Chaperones, 5, 52-61.
Malhotra, V., Shanley, T.P., Pittet, J.F., Welch, W.J. and Wong, H.R. (2001) Geldanamycin Inhibits NF-κB Activation and Interleukin-8 Gene Expression in Cultured Human Respiratory Epithelium. American Journal of Respiratory Cell and Molecular biology, 25, 92-97. https://doi.org/10.1165/ajrcmb.25.1.4384
Wong, H.R., Ryan, M. and Wispé, J.R. (1997) Stress Response Decreases NF-kappaB Nuclear Translocation and Increases I-KappaBalpha Expression in A549 Cells. Journal of Clinical Investigation, 99, 2423-2428. https://doi.org/10.1172/JCI119425
Whitesell, L. and Cook, P. (1996) Stable and Specific Binding of Heat Shock Protein 90 by Geldanamycin Disrupts Glucocorticoid Receptor Function in Intact Cells. Molecular Endocrinology, 10, 705-712. https://doi.org/10.1210/mend.10.6.8776730
Bamberger, C., Wald, M., Bamberger, A. and Schulte, H. (1997) Inhibition of Mineralocorticoid and Glucocorticoid Receptor Function by the Heat Shock Protein 90-Binding Agent Geldanamycin. Molecular and Cellular Endocrinology, 131, 233- 240. https://doi.org/10.1016/s0303-7207(97)00115-9
Fliss, A., Benzeno, S., Rao, J. and Caplan, A. (2000) Control of Estrogen Receptor Ligand Binding by Hsp90. Journal of Steroid Biochemistry and Molecular Biology, 72, 223-230. https://doi.org/10.1016/s0960-0760(00)00037-6
Neckers, L., Schulte, T. and Mimnaugh, E. (1999) Geldanamycin as a Potential Anti-Cancer Agent, Its Molecular Target and Biochemical Activity. Investigational New Drugs, 17, 361-373. https://doi.org/10.1023/a:1006382320697
Sugita, T., Tanaka, S., Murakami, T., Miyoshi, H. and Ohnuki, T. (2008) Immunosuppressive Effects of the Heat Shock Protein 90-Binding Antibiotic Geldanamycin. Biochemistry and Molecular Biology International, 47, 587-595. https://doi.org/10.1080/15216549900201633
Grenert, J., Sullivan, W., Fadden, P., Haystead, T., Clark, J., et al. (1997) The Amino-Terminal Domain of Heat Shock Protein 90 (Hsp90) That Binds Geldanamycin Is an ATP/ADP Switch Domain That Regulates Hsp90 Conformation. Journal of Biological Chemistry, 272, 23843-23850. https://doi.org/10.1074/jbc.272.38.23843
Mandler, R., Wu, C., Sausville, E., Roettinger, A., Newman, D., et al. (2000) Immunoconjugates of Geldanamycin and Anti-HER2 Monoclonal Antibodies, Antiproliferative Activity on Human Breast Carcinoma Cell Lines. Journal of the National Cancer Institute, 92, 1573-1581. https://doi.org/10.1093/jnci/92.19.1573
Nimmanapalli, R., O’Bryan, E. and Bhalla, K. (2001) Geldanamycin and Its Analogue 17-Allylamino-17-Demethoxygeldanamycin Lowers Bcr-Abl Levels and Induces Apoptosis and Differentiation of Bcr-Abl-Positive Human Leukemic Blasts. Cancer Research, 61, 1799-1804.
Yang, J., Yang, J.M., Iannone, M., Shih, W., Lin Y. and Hait, W. (2001) Disruption of the EF-2 Kinase/Hsp90 Protein Complex: A Possible Mechanism to Inhibit Glioblastoma by Geldanamycin. Cancer Research, 61, 4010-4016.
Murphy, P., Sharp, A., Shin, J., Gavrilyuk, V., Dello, C., et al. (2002) Suppressive Effects of Ansamycins on Inducible Nitric Oxide Synthase Expression and the Development of Experimental Autoimmune Encephalomyelitis. Journal of Neuroscience Research, 67, 461-470. https://doi.org/10.1002/jnr.10139
Fukuyo, Y., Hunt, C.R. and Horikoshi, N. (2010) Geldanamycin and Its Anti-Cancer Activities. Cancer Letters, 290, 24-35. https://doi.org/10.1016/j.canlet.2009.07.010
Dey, A. and Cederbaum, A.I. (2007) Geldanamycin, an Inhibitor of Hsp90 Increases Cytochrome P450 2E1 Mediated Toxicity in HepG2 Cells through Sustained Activation of the p38MAPK Pathway. Archives of Biochemistry and Biophysics, 461, 275-286. https://doi.org/10.1016/j.abb.2007.02.014
Clark, C.B., Rane, M.J., El Mehdi, D., Miller, C.J., Sachleben, L.R., et al. (2009) Role of Oxidative Stress in Geldanamycin-Induced Cytotoxicity and Disruption of Hsp90 Signaling Complex. Free Radical Biology and Medicine, 47, 1440-1449. https://doi.org/10.1016/j.freeradbiomed.2009.08.012
Tian, Z.Q., Liu, Y.Q., Zhang, D., et al. (2004) Synthesis and Biological Activities of Novel 17-Aminogeldanamycin Derivatives. Bioorganic and Medicinal Chemistry, 12, 5317-5329. https://doi.org/10.1016/j.freeradbiomed.2009.08.012
Rastelli, G., Tian, Z.Q., Wang, Z., Myles, D. and Liu, Y. (2005) Structure-Based Design of 7-Carbamate Analogs of Geldanamycin. Bioorganic and Medicinal Chemistry Letters, 15, 5016-5021. https://doi.org/10.1016/j.bmcl.2005.08.013
Banerji, U., Judson, I. and Workman, P. (2003) The Clinical Applications of Heat Shock Protein Inhibitors in Cancer-Present and Future. Current Cancer Drug Targets, 3, 385-390. https://doi.org/10.2174/1568009033481813
Li, Z., Jia, L., Wang, J., Wu, X., Hao, H., et al. (2014) Design, Synthesis and Biological Evaluation of 17-Arylmethylamine-17-Demethoxygeldanamycin Derivatives as Potent Hsp90 Inhibitors. European Journal of Medicinal Chemistry, 85, 359-370. https://doi.org/10.1016/j.ejmech.2014.07.101
Heath, E.I., Hillman, D.W., Vaishampayan, U., Sheng, S., Sarkar, F., et al. (2008) A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Hormone-Refractory Metastatic Prostate Cancer. Clinical Cancer Research, 14, 7940- 7946. https://doi.org/10.1158/1078-0432.ccr-08-0221
Pacey, S., Wilson, R.H., Walton, M., Eatock, M.M., Hardcastle, A., et al. (2011) A Phase I Study of The Heat Shock Protein 90 Inhibitor Alvespimycin (17-DMAG) Given Intravenously to Patients with Advanced Solid Tumors. Clinical Cancer Research, 17, 1561-1570. https://doi.org/10.1158/1078-0432.ccr-10-1927
Oh, W.K., Galsky, M.D., Stadler, W.M., Srinivas, S., Chu, F., et al. (2011) Multicenter Phase II Trial of The Heat Shock Protein 90 Inhibitor, Retaspimycin Hydrochloride (IPI-504), in Patients with Castration-Resistant Prostate Cancer. Urology, 78, 626-630. https://doi.org/10.1016/j.urology.2011.04.041
Neckers, L. (2002) Hsp90 Inhibitors as Novel Cancer Chemotherapeutic Agents. Trends in Molecular Medicine, 8, S55-S61. https://doi.org/10.1016/s1471-4914(02)02316-x
Jung, E.H., Hwang, J.S., Kwon, M.Y., Kim, K.H., Cho, H., et al. (2016) A Tryptamine-Paeonol Hybridization Compound Inhibits LPS-Mediated Inflammation in BV2 Cells. Neurochemistry International, 100, 35-43. https://doi.org/10.1016/j.neuint.2016.08.010