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Phenyldiazenylphenylpicolinamide 유도체들의 방향성탄화수소 수용체의 길항 활성에 대한 연구

Study on the Antagonistic Activity on Arylhydrocarbon Receptor of Phenyldiazenylphenylpicolinamides

  • 윤완영 (서원대학교 임상건강운동학과) ;
  • 이효성 (서원대학교 제약식품공학부)
  • Yoon, Wan-Young (Dept. of Clinical Exercise Physiology, Seowon University) ;
  • Lee, Hyosung (School of Food and Pharmaceutical Science & Engineering, Seowon University)
  • 투고 : 2018.12.12
  • 심사 : 2019.01.20
  • 발행 : 2019.01.28

초록

방향성탄화수소 수용체(Arylhydrocarbon Receptor, AhR)은 리간드에 의해 활성화되어 체내 외래물질의 대사를 조절하는 전사인자다. 생체 내에서 AhR의 생리학적 역할은 오랜 기간 연구되어 왔으나 활성화를 유발하지 않는 길항제를 비롯하여 유효한 화학적 도구가 아직 개발되지 않아 기능 연구가 제한적이다. AhR이 다양한 질병의 발병기전에서 중요한 역할을 수행한다는 것이 보고됨에 따라 약물 표적으로서 유효하다고 판단되나 치료나 예방을 위한 유효한 약물은 아직 개발되지 않았다. 길항제로 알려진 화합물들은 낮은 농도에서는 활성이 있어 연구 목적으로 활용되고 있으나 높은 농도에서는 방향성 탄화수소를 활성화하는 부분적 agonist로 작용한다. 이에 AhR 활성화를 유도하지 않는 순수한 길항제의 개발이 필요하다. 본 연구에서는 이미 알려진 AhR 길항제의 골격인 phenyldiazenylphenylpicolinamide의 세 고리구조 중 두 고리구조에 존재하는 메틸 기들을 변형하여 활성을 평가하는 구조-활성 관계 연구를 통하여 새로운 길항제를 개발하고자 하였다.

Aryl hydrocarbon receptor (AhR) is the master regulator of xenobiotics metabolizing enzymes (XMEs). AhR is activated by aryl hydrocarbons upon binding then goes into the cell nucleus and acts as a transcription factor. Despite the role of AhR in human physiology has been investigated for a long while, it is yet to be understood mainly due to the lack of appropriate chemical agents. Furthermore, it has been reported that AhR is related to a wide range of pathogenesis. In addition, recent studies suggest that the study on the development of AhR antagonist may provide a valid therapeutic agent. Some known antagonists in current use are partially agonistic whereas a pure antagonist is still absent. In this study, two phenyl-ring structures of phenyldiazenylphenylpicolinamide has been modified into various structures and evaluated its impact on the AhR antagonistic activity to elucidate the structure-activity relationship.

키워드

DJTJBT_2019_v17n1_443_f0001.png 이미지

Scheme 1. Synthesis of phenyldiazenylphenylpicolinamide

Table 1. Biological effects of compounds on AhR.

DJTJBT_2019_v17n1_443_t0001.png 이미지

참고문헌

  1. K. M. Burbach, A. Poland & C. A. Bradfield. (1992). Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proceedings of the National Academy of Sciences, 89(17), 8185-8189. https://doi.org/10.1073/pnas.89.17.8185
  2. A. B. Okey, D. S. Riddick & P. A. Harper. (1994). Molecular biology of the aromatic hydrocarbon (dioxin) receptor. Trends in Pharmacological Sciences, 15(7), 226-232. https://doi.org/10.1016/0165-6147(94)90316-6
  3. C. Ma, J. L. Marlowe & A. Puga. (2009). The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways. EXS, 99, 231-257.
  4. E. J. Choi, D. G. Toscano, J. A. Ryan, N. Riedel & W. A. Toscano Jr. (1991). Dioxin induces transforming growth factor-alpha in human keratinocytes. The Journal of Biological Chemistry, 266(15), 9591-9597. https://doi.org/10.1016/S0021-9258(18)92861-9
  5. A. Levine-Fridman, L. Chen & C. J. Elferink. (2004). Cytochrome P4501A1 promotes G1 phase cell cycle progression by controlling aryl hydrocarbon receptor activity. Molecular Pharmacology, 65(2), 461-469. https://doi.org/10.1124/mol.65.2.461
  6. F. Yang & D. Bleich. (2004). Transcriptional regulation of cyclooxygenase-2 gene in pancreatic beta-cells. Journal of Biological Chemistry, 279(34), 35403-35411. https://doi.org/10.1074/jbc.M404055200
  7. J. Guo et al. (2004). Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice. Toxicology and Applied Pharmacology, 194(1), 79-89. https://doi.org/10.1016/j.taap.2003.09.002
  8. B. D. Abbott, G. H. Perdew & L. S. Birnbaum. (1989). Ah receptor in embryonic mouse palate and effects of TCDD on receptor expression. Toxicology and Applied Pharmacology, 126(1), 16-25. https://doi.org/10.1006/taap.1994.1085
  9. E. A. Thackaberry, E. J. Bedrick, M. B. Goens, L. Danielson, A. K. Lund, D. Gabaldon, S. M. Smith & M. K. Walker. (2003). Insulin regulation in AhR-null mice: embryonic cardiac enlargement, neonatal macrosomia, and altered insulin regulation and response in pregnant and aging AhR-null females. Toxicological Sciences, 76(2), 407-417. https://doi.org/10.1093/toxsci/kfg229
  10. P. Fernandez-Salguero et al. (1995). Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science, 268(5211), 722-726. https://doi.org/10.1126/science.7732381
  11. Y. F. Lu, M. Santostefano, B. D. Cunningham, M. D. Threadgill & S. Safe. (1996). Substituted flavones as aryl hydrocarbon receptor agonists and antagonists. Biochemical Pharmacology, 51(8), 1077-1087. https://doi.org/10.1016/0006-2952(96)00063-9
  12. J. E. Lee & S. Safe. (2000). 3',4'-dimethoxyflavone as an aryl hydrocarbon receptor antagonist in human breast cancer cells. Toxicological Sciences, 58(2), 235-242. https://doi.org/10.1093/toxsci/58.2.235
  13. J. J. Reiners Jr, R. Clift & P. Mathieu. (1999). Suppression of cell cycle progression by flavonoids: dependence on the aryl hydrocarbon receptor, Carcinogenesis, 20(2), 1561-1566. https://doi.org/10.1093/carcin/20.8.1561
  14. H. Lee. (2017). The impact of o-toluidinyl structure of 2-me th yl -4 -(2 -met hyl p he nyl di az enyl ) p he nyl picolinamide on the AhR antagonistic activity, Journal of Korea Convergence Society, 8(1), 115-121. https://doi.org/10.15207/JKCS.2017.8.1.115
  15. I. Azumaya, T, Okamoto, F. Imabeppu & H. Takayanagi. (2003). Simple and convenient synthesis of teriary benzanilides using dichlorotriphenylphosphorane, Tetrahedron, 59(123), 2325-2331. https://doi.org/10.1016/S0040-4020(03)00235-7