Synthesis, COX-1/2 inhibition and antioxidant activities of new oxicam analogues designed as potential chemopreventive agents

Berenika Marta Szczęśniak-Sięga; Katarzyna Gębczak; Tomasz Gębarowski; Jadwiga Maniewska

doi:10.18388/abp.2018_2614

Berenika Marta Szczęśniak-Sięga Department of Chemistry of Drugs, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland;
Katarzyna Gębczak Department of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland;
Tomasz Gębarowski Department of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland;
Jadwiga Maniewska Department of Chemistry of Drugs, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland;

DOI: https://doi.org/10.18388/abp.2018_2614

Keywords: synthesis, chemoprevention, antioxidant, COX, NSAIDs, oxicams

Abstract

Oxicams (e.g. piroxicam, meloxicam) are widely used nonsteroidal anti-inflammatory drugs (NSAIDs). A large body of evidence from epidemiological and preclinical studies has shown that NSAIDs have a chemopreventive effect on different types of cancer, especially in colorectal cancer. Moreover mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. What is more, inflammation induces reactive oxygen and nitrogen species, which cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. In this study, we discuss the synthesis and the resultant newly synthesised oxicam derivatives which are potentially chemopreventive, and at the same time antioxidant. Compound 9c with highest therapeutic index in the LoVo cancer cell line was found to be the most efficient at ROS scavenging activity in the condition of oxidative stress.

References

AI-Fayez M, Cai H, Tunstall R, Steward WP, Gescher AJ (2006) Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin. Cancer Chemother Pharmacol 58: 816-825. http://dx.doi.org/10.1007/s00280-006-0228-3

Boghossian S, Hawash A (2012) Chemoprevention in colorectal cancer - where we stand and what we have learned from twenty years’ experience. Surgeon 10: 43-52.

https://doi.org/10.1016/j.surge.2011.07.003

Cook N, Lee I, Zhang S, Moorthy M, Buring J (2013) Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 159: 77-85. https://doi.org/10.7326/0003-4819-159-2-201307160-00002

Dannenberg AJ, Altorki NK, Boyle JO, Dang Ch, Howe LR, Weksler BB, Subbaramaiah K (2001) Cyclo-oxygenase 2:a pharmacological target for the prevention of cancer. Lancet Oncol 2: 544–551. https://doi.org/10.1016/S1470-2045(01)00488-0

Dhingra AK, Chopra B, Dass R, Sanjeev, Mittal SK (2014) A review on COX and their inhibitors: Present and future, IPP 2 (4): 470-485.

Eruslanov E, Kusmartsev S (2010) Identification of ROS using oxidized DCFDA and flow-cytometry. Met Mol Biol 594: 57–72. https://doi.org/10.1007/978-1-60761-411-1_4

Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194: 7-15. Doi: 10.1083/jcb.201102095

Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62 (2): 233–244.

Gravitz L (2011) First line of defence. Combinations of drugs are showing some promise as therapeutic agents that stop cancer before it starts. Nature 471: 5-7.

Greenspan EJ, Madigan JP, Boardman LA, Rosenberg DW (2011) Ibuprofen inhibits activation of nuclear {beta}-catenin in human colon adenomas and induces the phosphorylation of GSK-3{beta}. Cancer Prev Res 4 (1): 161-171. https://doi.org/10.1158/1940-6207.CAPR-10-0021

Gupta RA, Dubois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1: 11-21. https://doi.org/10.1038/35094017

Harris R, Beebe-Donk J, Alshafie G (2008) Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 8: 237. https://doi.org/10.1186/1471-2407-8-237

Kundu JK, Surh Y-J (2008) Inflammation: Gearing the journey to cancer. Mut Res 659: 15–30. https://doi.org/10.1016/j.mrrev.2008.03.002.

Krzyżak E, Szczęśniak-Sięga B, Malinka W (2014) Synthesis and thermal behaviour of new benzo-1,2-thiazine long-chain aryl-piperazine derivatives. J Therm Anal Cal 115 (1): 793–802. doi: 10.1007/s10973-013-3185-1

Lee EJ, Choi EM, Kim SR, Park JH, Kim H, Ha KS, Kim YM, Kim SS, Choe M, Kim J-I, Han JA (2007) Cyclooxygenase-2 promotes cell proliferation, migration and invasion in U2OS human osteosarcoma cells. Exp Mol Med 39: 469-476. https://doi.org/10.1038/emm.2007.51

Loo AEK, Halliwell B (2012) Effects of hydrogen peroxide in a keratinocyte-fibroblast co-culture model of wound healing. Biochem Biophys Res Commun 423(2): 253–258. https://doi.org/10.1016/j.bbrc.2012.05.100

Lopez L, Selent J, Ortega R, Masaguer ChF, Dominguez E, Areias F, Brea J, Loza MI, Sanz F, Pastor M (2010) Synthesis, 3D-QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors. Chem Med Chem 5(8): 1300-1317.

Maniewska J, Szczęśniak-Sięga B, Poła A, Środa-Pomianek K, Malinka W, Michalak K (2014) The interaction of new piroxicam analogues with lipid bilayers – a calorimetric and fluorescence spectroscopic study. Acta Pol Pharm – Drug Res 71(6): 1004–1012.

Mansouri D, McMillan D, Roxburgh C, Crighton E, Horgan P (2013) The impact of aspirin, statins and ACE-inhibitors on the presentation of colorectal neoplasia in a colorectal cancer screening programme. Br J Cancer 109: 249–256. https://dx.doi.org/10.1038%2Fbjc.2013.292

Martin JE, Young GP, Leu RKL, HU Y (2013) Comparing the Effects of COX and Non-COX-inhibiting NSAIDs on Enhancement of Apoptosis and Inhibition of Aberrant Crypt Foci Formation in a Rat Colorectal Cancer Model. Anticancer Res 33(9): 3581-3588.

Muszalska I, Ciemniejewski MP, Lesniewska MA, Szkatuła D, Malinka W (2015) Forced Degradation and Photodegradation Studies of Pyrrolo[3,4-c]pyridine-1,3-dione Derivatives as Analgesic Active Compounds Using HPLC, UV and IR Spectrometry, and HPLC/MS Methods. J AOAC Inter 98 (5): 1248-1259. https://doi.org/10.5740/jaoacint.14-240

Park JH, McMillan DC, Horgan PG, Roxburgh CS (2014) The im¬pact of anti-inflammatory agents on the outcome of patients with colorectal cancer. Cancer Treat Rev 40: 68–77. doi: 10.1016/j. ctrv.2013.05.006

Paudel S, Acharya S, Kim KM, Cheon SH (2016) Design, synthesis, and biological evaluation of arylpiperazine-benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities. Bioorg Med Chem 24(9): 2137-2145. Doi: 10.1016/j.bmc.2016.03.044.

Piazuelo E, Lanas A (2015) NSAIDS and gastrointestinal cancer. Prostaglandins other Lipid Mediat 120: 91–96. http://dx.doi.org/10.1016/j.prostaglandins.2015.06.001

Raja SB, Rajendiran V, Kasinathan NK, Amrithalakshmi P, Venkatabalasubramanian S, Murali MR, Devaraj H, Devaraj SN (2017) Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression. Food Chem Toxicol 106: 92-106. http://dx.doi.org/10.1016/j.fct.2017.05.006

Romero-Canelón I, Mos M, Sadler PJ (2015) Enhancement of Selectivity of an Organometallic Anticancer Agent by Redox Modulation. J Med Chem 58: 7874−7880. DOI: 10.1021/acs.jmedchem.5b00655

Rostom A, Dube C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D (2007) Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 146: 376-389. Doi: 10.7326/0003-4819-146-5-200703060-00010

Rothwell P, Fowkes F, Belch J, Ogawa H, Warlow Ch, Meade T (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trias. Lancet 377: 31–41. https://doi.org/10.1016/S0140-6736(10)62110-1

Rothwell P, Wilson M, Elwin C, Norrving B, Algra A, Warlow Ch, Meade T (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trias. Lancet 376: 1741–1750. https://doi.org/10.1016/S0140-6736(10)61543-7

Sahin I, Hassan M, Garrett Ch (2014) Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: Current state-of-the science. Cancer Lett 345: 249–257. http://dx.doi.org/10.1016/j.canlet.2013.09.001

Sen S, Chakraborty R (2011) The Role of Antioxidants in Human Health. In Oxidative Stress: Diagnostics, Prevention, and Therapy Andreescu and Hepel, pp 1-37; ACS Symposium Series; American Chemical Society: Washington, DC. Doi: 10.1021/bk-2011-1083.ch001

Sporn MB (1976) Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 36: 2699–2702.

Szczęśniak-Sięga B, Maniewska J, Poła A, Środa-Pomianek K, Malinka W, Michalak K (2014) Synthesis of new Piroxicam derivatives and their influence on lipid bilayers. Acta Pol Pharm Drug Res 71: 1045-1050.

Thun MJ, Jacobs EJ, Patrono C (2012) The role of aspirin in cancer prevention. Nat Rev Clin Oncol. 9 (5): 259-267. Doi: 10.1038/nrclinonc.2011.199.

Tsioulias GJ, Rigas B (2015) NSAIDs and Colorectal Cancer Control: Promise and Challenges. Curr Pharmacol Rep 1 (5): 295–301. Doi:10.1007/s40495-015-0042-x.

Ulrich C, Bigler J, Potter J (2006) Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 6: 130-140. https://doi.org/10.1038/nrc1801

Wakeman Ch, Keenan J, Eteuati J, Hollington P, Eglinton T, Frizelle F (2017) Chemoprevention of colorectal neoplasia. ANZ J Surg 87(12): E228–E232. Doi: 10.1111/ans.13392.

Vane JR, Bakhle YS (2006) Cyclooxygenase 1 and 2. Annu Rev Pharmacol Toxicol 38: 97-120.

https://doi.org/10.1146/annurev.pharmtox.38.1.97

Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening.

Nat Protoc 1: 1112-1116. https://doi.org/10.1038/nprot.2006.179

Xiaoyun L, Lochhead P, Andrew MB, Chan T, Ogino S et al. (2012) Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival. N Engl J Med 367 (17): 1596–1606. Doi: 10.1056/NEJMoa1207756

Yoshimura A, Koski SR, Fuchs JM, Saito A, Nemykin VN, Zhdankin VV (2015) Saccharin-Based μ-Oxo Imidoiodane: A Readily Available and Highly Reactive Reagent for Electrophilic Amination. Chem Eur J 21(14): 5328-5331. Doi: 10.1002/chem.201500335

Zhou B, Liu ZF, Deng GG, Chen W, Li MY, Yang LJ, Li Y, Yang XD, Zhang HB (2016) Synthesis and antitumor activity of novel N-substituted tetrahydro-β-carboline-imidazolium salt derivatives. Org Biom Chem 14(39): 9423-9430. Doi: 10.1039/c6ob01495j