Journal of the Korean Applied Science and Technology (한국응용과학기술학회지)

The Korean Society of Applied Science and Technology (한국응용과학기술학회)
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Fusion anti-cancer drugs of cisplatin analogue and fatty acids for multi-targeted cancer treatment

시스플라틴과 지방산을 결합한 퓨전 항암제

  • Byeon, Hong-Ju (Department of Biotechnology, Korea National University of Transportation) ;
  • Lee, Hyang-Yeol (Department of Biotechnology, Korea National University of Transportation)
  • 변홍주 (한국교통대학교 생명공학과) ;
  • 이향렬 (한국교통대학교 생명공학과)
  • Received : 2018.11.30
  • Accepted : 2018.12.21
  • Published : 2018.12.31
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Abstract

Cispatin has become one of the most widely used anticancer drugs for decades. One of the drawback of cisplatin (II) complex is that it not only targets cancerous cells but also normal cells causing several serious side effects in patients. We have synthesized Pt(IV) complex that are needed to have the ability to kill target cells selectively in a short time before drug resistance develops. By introducing PDK inhibitor, butyric acid and valproic acid, on Pt complex, two fusion anti-cancer agents 3 and 4 have been synthesized and characterized their structures by nmr and mass spectrometer. MTT assay was performed with $Pt(IV)-Bu_2$ 3 and $Pt(IV)-Val_2$ 4 against MCF-7 cell line. As a result, cisplatin, Pt(IV) complexes 3 and 4 were treated, cell viabilities at $50{\mu}M$ cencentration were decreased to 39%, 54% and 84% respectively.

시스플라틴은 지난 몇 십년간 가장 많이 사용되고 있는 항암제 중 하나이다. 2가의 시스플라틴의 가장 큰 단점은 암세포 뿐만 아니라 정상세포도 공격하여 부작용을 나타낸다. 본 연구에서는 이러한 단점을 줄이기 위해 목표로 한 타겟을 공격하여 빠른 시간 내에 암세포를 죽일 수 있는 4가의 백금화합물 3과 4를 합성하였다. 합성된 $Pt(IV)-Bu_2$ 3 and $Pt(IV)-Val_2$ 4는 NMR과 질량분석기를 통하여 구조를 확인하였다. 합성된 Pt(IV) 화합물 3과 4는 위암세포주인 MCF-7을 대상으로 한 MTT assay를 통해 항암효과를 조사하였다. 그 결과 시스플라틴은 39%, $Pt(IV)-Bu_2$ 3와 $Pt(IV)-Val_2$ 4는 $50{\mu}M$ 농도에서 각각 54%와 84%의 세포사멸을 보였다.

Keywords

HGOHBI_2018_v35n4_1386_f0001.png 이미지

Fig. 1. Chemical structure of Mitaplatin and its mechanism of action.

HGOHBI_2018_v35n4_1386_f0002.png 이미지

Fig. 2. NMR spectra of Pt(IV)-Bu2 compound 3.

HGOHBI_2018_v35n4_1386_f0003.png 이미지

Fig. 3. NMR spectra of Pt(IV)-Val2 compound 4.

HGOHBI_2018_v35n4_1386_f0004.png 이미지

Fig. 4. Cytotoxic effect of platinumcompounds .

HGOHBI_2018_v35n4_1386_f0005.png 이미지

Fig. 5. Chemical structures and mechanism of action of Pt(IV) compounds.

References

  1. P. M. Takahara, A. C. Rosenzweig, C. A. Frederick, S. J.. Lippard, "Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin", Nature Vol. 377, pp. 649-652, (1995). https://doi.org/10.1038/377649a0
  2. M. R. Reithofer, A. Schwarzinger, S. M. Valiahdi, M. Galanski, M. A. Jakupec, B. K. Keppler, "Novel bis(carboxylato) dichlorido(ethane-1,2-diamine)platinum(IV) complexes with exceptionally high cytotoxicity", Journal of Inorganic Biochemistry, Vol. 102, pp. 2072-2077, (2008). https://doi.org/10.1016/j.jinorgbio.2008.07.006
  3. W. H. Ang, S. Pilet, R. Scopelliti, F. Bussy, L. Juillerat-Jeanneret, P. J. Dyson, "Synthesis and characterization of platinum(IV) anticancer drugs with functionalized aromatic carboxylate ligands: influence of the ligands on drug efficacies and uptatke", Journal of medicinal Chemistry, Vol. 48, pp. 8060-8069, (2005). https://doi.org/10.1021/jm0506468
  4. W. H. Ang, I. Khalaila, C. S. Allardyce, L. Juillerat-Jeanneret, P. J. Dyson, "Rational design of platinum(IV) compounds to overcome glutathione-Stransferase meditated drug resistance", Journal of American Chemical Society, Vol. 127, pp. 1382-1383, (2005). https://doi.org/10.1021/ja0432618
  5. S. Dhar, Z. Liu, J. Thomale, H. J. Dai, S. J. Lippard, "Targeted Single Wall Carbon Nanotube Meditated Pt(IV) Prodrug Delivery Using Folate as a Homing Device", Journal of American Chemical Society, Vol. 130, pp. 11467-11476, (2009).
  6. S. Dhar, S. Lippard, "Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate", Proceeding of the National Academy of Sciences, Vol. 106, pp. 22199-22204, (2009). https://doi.org/10.1073/pnas.0912276106
  7. K. R. Barnes, A. Kutikov, S. J. Lippard, "Synthesis, characterization, and cytotoxicity of a serious of estrogen-tethered platinum (IV) complexes", Chemical Biology, Vol. 11, pp. 557-564, (2004). https://doi.org/10.1016/j.chembiol.2004.03.024
  8. V. Novohradsk, L. Zerzankova, J. Stepankova, O. Vrana, R. Raveendran, D. Gibson, J. Kasparkova, V. Brabec, "New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells", Biochemical Pharmacology, Vol. 95, pp. 133-144, (2015). https://doi.org/10.1016/j.bcp.2015.04.003
  9. M. Galanski, B. K. Keppler, "Synthesis and characterization of new ethylenediamine platinium(IV) complexes containing lipophilic carboxylate ligands", Metal-Based Drugs, Vol. 2, pp. 57-63, (1995). https://doi.org/10.1155/MBD.1995.57
  10. M. Galanski, B. K. Keppler, "Carboxylation of dihydroxoplatinium(IV) complexes via a new synthetic pathway", Inorganic Chemistry, Vol 35, pp. 1709-1711, (1996). https://doi.org/10.1021/ic9509490
  11. M. G. Vander Heiden, L.C. Cantley, C. B. Thompson, "Understanding the Warburg effect: the metabolic requirements of cell proliferation", Science, Vol. 324, pp. 1029-1033, (2009). https://doi.org/10.1126/science.1160809
  12. M. Galanski, V. B. Arion, M. A. Jakupec, B. K. Keppler, "Recent Developments in the Field of Tumor-Inhibiting Metal Complexes", Current Pharmaceutical Design, Vol. 9, pp. 2078-2089, (2003). https://doi.org/10.2174/1381612033454180
  13. R. He, Y. Chen, Y. Chen, A. V. Ougolkov, J. S. Zhang, D. N. Savoy, D. D. Billadeau, A. P. Kozikowski, "Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone diacetylase inhinitors as anticancer agents", Journal of Medicinal Chemistry, Vol. pp. 1347-1356, (2010).
  14. C. M. Giandomeico, M. J. Abrams, B. A. Murrer, J. F. Vollano, M. I. Rheinheimer, S. B. Wyer, G. E. Bossard, J. D. Higgins III, "Carboxylation of Kinetically Inert Platinum(IV) hydroxy Complexes. An Entree into Orally Active Platinum(IV) Antitumor Agents:, Inorg. Chem. Vol. 34, pp 1015-1021 (1995). https://doi.org/10.1021/ic00109a004
  15. M. Kartalou, J. M. Essigmann, "Mechanism of resistance to cisplatin", Mutation Research, Vol. 478, pp. 23-43, (2001). https://doi.org/10.1016/S0027-5107(01)00141-5
  16. A. Nemirovski, Y. Kasherman, Y. Tzaraf, D. Gibson, "Reduction of cis,trans,cis-[$PtCl_2(OCOCH_3)_2(NH_3)_2$] by Aqueous Extracts of Cancer Cells", Journal of Medicinal Chemistry, Vol. 50, pp. 5554-5556, (2007). https://doi.org/10.1021/jm070740j