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Int. J. Mol. Sci. 2018, 19(5), 1453; https://doi.org/10.3390/ijms19051453

Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin

1
Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 161, Section 6, Minquan East Road, Taipei 114, Taiwan
2
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore
3
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
4
Department of Orthopaedics, Tri-Service General Hospital, National Defense Medical Center, No. 161, Section 6, Minquan East Road, Taipei 114, Taiwan
5
School of Pharmacy, National Defense Medical Center, No. 161, Section 6, Minquan East Road, Taipei 114, Taiwan
6
Rheumatology/Immunology and Allergy, Department of Medicine, Armed Forces Taoyuan General Hospital; Taoyuan 325, Taiwan
7
Institute of Cellular and System Medicine, National Health Research Institute, No. 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan
8
Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, Minquan East Road, Taipei 114, Taiwan
9
Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, No. 5, Fusing St., Gueishan Township, Tao-Yuan County 333, Taiwan
*
Author to whom correspondence should be addressed.
Received: 20 April 2018 / Revised: 10 May 2018 / Accepted: 11 May 2018 / Published: 14 May 2018
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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Abstract

In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)–nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics. View Full-Text
Keywords: arthritis; osteoarthritis; rheumatoid arthritis; small-molecule inhibitor; chondrocytes; tumor necrosis factor-alpha; inflammation arthritis; osteoarthritis; rheumatoid arthritis; small-molecule inhibitor; chondrocytes; tumor necrosis factor-alpha; inflammation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Liu, F.-C.; Lu, J.-W.; Chien, C.-Y.; Huang, H.-S.; Lee, C.-C.; Lien, S.-B.; Lin, L.-C.; Chen, L.W.; Ho, Y.-J.; Shen, M.-C.; Ho, L.-J.; Lai, J.-H. Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin. Int. J. Mol. Sci. 2018, 19, 1453.

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