Journal of the Korea Convergence Society (한국융합학회논문지)

Korea Convergence Society (한국융합학회)
권호 표지
DOI QR코드

DOI QR Code

The Impact of o-Toluidinyl Structure of 2-Methyl-4-(2-methylphenyldiazenyl)phenyl picolinamide on the AHR Antagonistic Activity

2-Methyl-4-(phenyldiazenyl)phenyl picolinamide의 o-toluidinyl 구조가 AHR 길항저해 활성에 미치는 영향

  • Lee, Hyosung (Department of Pharmaceutical Science & Engineering, Seowon University)
  • Received : 2016.11.23
  • Accepted : 2017.01.20
  • Published : 2017.01.28
Download PDF
⟨ Previous Next ⟩

Abstract

AHR is a transcription factor activated by aryl hydrocarbons, regulating the expression of XMEs (xenobiotics Metabolizing Enzymes). Even though the role of AHR in human physiology has been intensively investigated for the past decades, our understandings are still largely limited due to the deficiency of adequate chemical agents. In addition, it has been demonstrated that AHR correlates to pathogeneses for some diseases. Furthermore, emerging data suggest that the study on the AHR may provide a valid therapeutic target. Classical antagonists in current use are reported to be partial agonistic whereas a pure antagonist is demanded. In this study, o-toluidinyl ring structure of 2-methyl-4-(2-methylphenyldiazenyl)phenyl picolinamide has been modified into various structures to optimize the AHR antagonistic activity by means of convergence study of organic synthesis and molecular biology.

AHR(Aryl Hydrocarbon Receptor, 방향성탄화수소 수용체)은 리간드에 의해 활성화되어 체내 외래물질의 대사를 조절하는 전사인자다. 생체 내에서 AHR의 생리학적 역할은 오랜 기간 연구되어 왔으나 antagonist를 비롯한 적절한 화학적 도구의 부재로 그 역할 규명이 제한되어 있다. AHR이 암을 비롯한 여러 질병의 발병기전에 관여되어 있다는 것이 밝혀짐에 따라 유효한 약물 표적으로 간주되나 화학적 도구의 부재로 인해 치료용 약물 개발 역시 제한되어 있다. 기존 antagonist 들은 저농도에서는 활성이 있으나 높은 농도에서는 AHR의 활성화를 유도하는 부분적 antagonist이므로 순수 저해활성을 가지는 신규 antagonist의 개발이 필요하다. 본 연구에서는 2-methyl-4-(2-methylphenyldiazenyl)phenyl picolinamide의 o-toluidinyl 고리구조의 변경하여 활성을 평가하는 유기화학과 분자생물학의 융합연구를 통하여 o-toluidinyl 구조를 최적화하였다.

Keywords

References

  1. K. M. Burbach, A. Poland and C. A. Bradfield, "Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor", Proceedings of the National Academy of Sciences, USA, Vol. 89, No. 17, pp. 8185-8189 1992. https://doi.org/10.1073/pnas.89.17.8185
  2. A. B. Okey, D. S. Riddick and P. A. Harper, "Molecular biology of the aromatic hydrocarbon (dioxin) receptor", Trends in Pharmacological Sciences, Vol. 15, No. 7, pp. 226-232 1994. https://doi.org/10.1016/0165-6147(94)90316-6
  3. C. Ma, J. L. Marlowe and A. Puga, "The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways", EXS Vol. 99, pp. 231-257, 2009.
  4. E. J. Choi, D. G. Toscano, J. A. Ryan, N. Riedel and W. A. Toscano, Jr., "Dioxin induces transforming growth factor-alpha in human keratinocytes", The Journal of Biological Chemistry, Vol. 266, No. 15, pp. 9591-9597, 1991.
  5. A. Levine-Fridman, L. Chen and C. J. Elferink, "Cytochrome P4501A1 promotes G1 phase cell cycle progression by controlling aryl hydrocarbon receptor activity", Molecular Pharmacology, Vol. 65, No. 2, pp. 461-469, 2004. https://doi.org/10.1124/mol.65.2.461
  6. F. Yang and D. Bleich, "Transcriptional regulation of cyclooxygenase-2 gene in pancreatic beta-cells", Journal of Biological Chemistry, Vol. 279, No. 34, pp. 35403-35411, 2004. https://doi.org/10.1074/jbc.M404055200
  7. J. Guo, M. Sartor, S. Karyala, M. Medvedovic, S. Kann, A. Puga, P. Ryan and C. R. Tomlinson, "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, Vol. 194, No. 1, pp. 79-89, 2004. https://doi.org/10.1016/j.taap.2003.09.002
  8. B. D. Abbott, G. H. Perdew and L. S. Birnbaum, "Ah receptor in embryonic mouse palate and effects of TCDD on receptor expression", Toxicology and Applied Pharmacology, Vol. 126, No. 1, pp. 16-25, 1989. 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 and M. K. Walker, "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, Vol. 76, No. 2, pp. 407-417, 2003. https://doi.org/10.1093/toxsci/kfg229
  10. P. Fernandez-Salguero, T. Pineau, D. M. Hilbert, T. McPhail, S. S. Lee, S. Kimura, D. W. Nebert, S. Rudikoff, J. M. Ward and F. J. Gonzalez, "Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor", Science, Vol. 268, No. 5211, pp. 722-726, 1995. https://doi.org/10.1126/science.7732381
  11. H. Lee, "Development of Novel AHR Antagonists", Doctoral Dissertation, University of Kentucky, 2010.
  12. Y. F. Lu, M. Santostefano, B. D. Cunningham, M. D. Threadgill and S. Safe, "Substituted flavones as aryl hydrocarbon receptor agonists and antagonists", Biochemical Pharmacology, Vol. 51, No. 8, pp. 1077-1087, 1996. https://doi.org/10.1016/0006-2952(96)00063-9
  13. J. E. Lee and S. Safe, "3',4'-dimethoxyflavone as an aryl hydrocarbon receptor antagonist in human breast cancer cells", Toxicological Sciences, Vol. 58, No. 2, pp. 235-242, 2000. https://doi.org/10.1093/toxsci/58.2.235
  14. J. J. Reiners, Jr., R. Clift and P. Mathieu, "Suppression of cell cycle progression by flavonoids: dependence on the aryl hydrocarbon receptor", Carcinogenesis, Vol. 20, No. 8, pp. 1561-1566, 1999. https://doi.org/10.1093/carcin/20.8.1561
  15. B. D. Cunningham, M. D. Threadgill, P. W. Groundwater, I. L. Dale and J. A. Hickman, "Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases", Anticancer Drug Design, Vol. 7, No. 5, pp. 365-384, 1992.
  16. E. Y. Choi, H. Lee, R. W. Dingle, K. B. Kim and H. I. Swanson, "AHR-based Therapeutic Agents", Molecular and Cellular Pharmacology, Vol. 4, No. 2, pp. 53-60, 2012