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Medicinal Chemistry Research

, Volume 27, Issue 2, pp 412–419 | Cite as

Synthesis and cytotoxicity of pyrido[4,3-b]carbazole alkaloids against HCT-116 and HL-60 cells

  • Tomoki Itoh
  • Noriyuki Hatae
  • Takashi Nishiyama
  • Tominari Choshi
  • Satoshi Hibino
  • Teruki Yoshimura
  • Minoru Ishikura
Original Research
  • 151 Downloads

Abstract

Ellipticine, olivacine, and their five reduced natural variants were synthesized via a palladium-catalyzed tandem cyclization/cross-coupling reaction as the key step. In addition, a previously unknown conformer of janetine was obtained through conformational inversion of the D ring in janetine. Because there are few synthetic approaches for reduced natural variants, little is known about the biological activities of these compounds. Six synthetic natural alkaloids and five of their derivatives were evaluated for their antiproliferative activity against HCT-116 and HL-60 cells. The activities of variants with the D-reduced ring or without the C(11)-Me group were lower than those of ellipticine. The conformer of guatambuine showed higher activities than guatambuine.

Keywords

Pyrido[4,3-b]carbazole alkaloids Cytotoxicity HCT-116 cell HL-60 cell 

Abbreviations

IC50

Half maximal inhibitory concentration

MTT

Thiazolyl blue tetrazolium bromide

WST-1

Water-soluble tetrazolium salt-1

Notes

Acknowledgements

This study was supported in part by a Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Sciences (No. 26460012 for M. I., and No. 17K08369 for N. H.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2068_MOESM1_ESM.pdf (7 mb)
Supplementary Information

References

  1. Alvarez M, Joule JA (2001) Ellipticine, uleine, apparicine, and related alkaloids. Alkaloids 57:235–273PubMedGoogle Scholar
  2. Auclair C (1987) Multimodal action of antitumor agents on DNA: ellipticine series. Arch Biochem Biophys 259:1–14CrossRefPubMedGoogle Scholar
  3. Canals A, Purciolas M, Aymami J, Coll M (2005) The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs. Acta Crystallogr Sect D 61:1009–1012CrossRefGoogle Scholar
  4. Charcosset JY, Salles B, Jacquemin-Sablon A (1983) Uptake and cytofluorescence localization of ellipticine derivatives in sensitive and resistant Chinese hamster lung cells. Biochem Pharmacol 32:1037–1044CrossRefPubMedGoogle Scholar
  5. Dalla Via L, Gia O, Marciani Magno Da Settimo SA, Primofiore G, Da Settimo F, Simorini F, Marini AM (2002) Dialkylaminoalkylindolonaphthyridines as potential antitumor agents: synthesis, cytotoxicity and DNA binding properties. Eur J Med Chem 37:475–486CrossRefPubMedGoogle Scholar
  6. Deane FM, O’Sullivan EC, Maguire AR, Gilbert J, Sakoff JA, McCluskey A, McCarthy FO (2013) Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. Org Biomol Chem 11:1334–1344CrossRefPubMedGoogle Scholar
  7. De Simone CA, Malta VRS, Humberto MMS, Porto KRA, Sant’Ana AEG (2006) Crystal structure of 1,2,5-trimethyl-1,2,3,4-tetrahydropyrido[4,3-b]carbazole (guatambuine), C18H20N2, from Aspidosperma subincanum Mart. Z Kristallogr New Cryst Struct 221:233–234.  https://doi.org/10.1524/ncrs.2006.0052 Google Scholar
  8. Goodwin S, Smith AF, Horning EC (1959) Alkaloids of ochrosia elliptica labill. J Am Chem Soc 81:1903–1908CrossRefGoogle Scholar
  9. Gopal M, Shahabuddin MS (2004) Biological properties of 8-methoxypyrimido[4’,5’,4,5]thieno(2,3-b)quinolone-4(3H)-one, a new class of DNA intercalating drugs. Indian J Med Res 119:198–205PubMedGoogle Scholar
  10. Gorczyca W, Gong J, Ardelt B, Traganos F, Darzynkiewicz Z (1993) The cell cycle related defferences in susceptibility of HL-60 cells to apotosis induced by various antitumor agents. Cancer Res 53:3186–3192PubMedGoogle Scholar
  11. Gribble GW, Saulnier MG (1985) Syntheses of ellipticine and related pyridocarbazole alkaloids. Heterocycles 23:1277–1315CrossRefGoogle Scholar
  12. Guillonneau C, Nault A, Raimbaud E, Léonce S, Kraus-Berthier L, Pierré A, Goldstein S (2005) Cytotoxic and antitumoral properties in a series of new, ring D modified, olivacine analogs. Bioorg Med Chem 13:175–184CrossRefPubMedGoogle Scholar
  13. Hewlins MJ, Oliveria-Campos AM, Shannon PV (1984) Synthetic approaches to ellipticine derivatives and analogs of 6H-pyrido[4,3-b]carbazole. Synthesis 289–302Google Scholar
  14. Ishikura M, Hino A, Yaginuma T, Agata I, Katagiri N (2000) A novel entry to pyrido[4,3-b]carbazoles: an efficient synthesis of ellipticine. Tetrahedron 56:193–207CrossRefGoogle Scholar
  15. Ishikura M, Takahashi N, Yamada K, Abe T, Yanada R (2008) Formal synthesis of olivacine via indolylborate. Helv Chim Acta 91(10):1828–1837CrossRefGoogle Scholar
  16. Ishiyama M, Shiga M, Sasamoto K, Mizoguchi M, He P (1993) A new sulfonated tetrazolium salt that produces a highly water-solble formazan dye. Chem Pharm Bull 41:1118–1122CrossRefGoogle Scholar
  17. Itoh T, Abe T, Choshi T, Nishiyama T, Yanada R, Ishikura M (2016) Concise total syntheses of pyrido[4,3-b]carbazole alkaloids using copper-mediated 6-electrocyclization, Eur J Org Chem 2290–2299Google Scholar
  18. Kansal VK, Potier P (1986) Biogenetic, synthetic and biochemical aspects of ellipticine, an antitumor alkaloid. Tetrahedron 42:2389–2408CrossRefGoogle Scholar
  19. Khayat D, Borel C, Azab M, Paraisot D, Malaurie E, Bouloux C, Weil M (1992) Phase I study of datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion. Cancer Chemother Pharmacol 30:226–228CrossRefPubMedGoogle Scholar
  20. Knölker H-J, Reddy KR (2002) Isolation and synthesis of biologically active carbazole alkaloids. Chem Rev 102:4303–4428CrossRefPubMedGoogle Scholar
  21. Kohn KW, Waring MJ, Glaubiger D, Friedman CA (1975) Intercalative binding of ellipticine to DNA. Cancer Res 35:71–76PubMedGoogle Scholar
  22. Kraus-Berthier L, Guilbaud N, Léonce S, Parker T, Genissel P, Guillonneau C, Goldstein S, Atassi G, Pierré A (2002) Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug. Cancer Chemother Pharmacol 50:95–103CrossRefPubMedGoogle Scholar
  23. Miller CM, McCarthy FO (2012) Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles. RSC Adv 2:8883–8918CrossRefGoogle Scholar
  24. Monnot M, Mauffret O, Simon V, Lescot E, Psaume B, Saucier JM, Charra M, Belehradek J, Fermandjian S (1991) DNA-drug recognition and effects on topoisomeraseII-mediated cytotoxicity. A three-mode binding model for ellipticine derivatives. J Biol Chem 266:1820–1829PubMedGoogle Scholar
  25. Montoia A, Rocha e Silva LFR, Torres ZE, Costa DS, Henrique MC, Lima ES, Vasconcellos MC, Souza RCZ, Costa MRF, Grafov A, Grafova I, Eberlin MN, Tadei WP, Amorim RCN, Pohlit AM (2014) Antiplasmodial activity of synthetic ellipticine derivatives and an isolated analog. Bioorg Med Chem Lett 24:2631–2634CrossRefPubMedGoogle Scholar
  26. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  27. Ohashi M, Oki T (1996) Ellipticine and related anticancer agents. Exp Opin Ther Patents 6:1285–1294.  https://doi.org/10.1517/13543776.6.12.1285 CrossRefGoogle Scholar
  28. O’Sullivan EC, Miller CM, Dean FM, McCarthy FO (2013) Emerging targets in the bioactivity of ellipticine and derivatives. Stud Nat Prod Chem 39:189–232CrossRefGoogle Scholar
  29. Sainsbury M (1977) The synthesis of 6H-pyrido[4,3-b]carbazoles. Synthesis 437–448Google Scholar
  30. Schmutz J, Hunzicker F (1958) Alkaloids of Aspidosperma Olivaceum. Pharm Acta Helv 33:341–347PubMedGoogle Scholar
  31. Shenoy S, Vasania VS, Gopa Ml, Mehta A (2007) 8-Methyl-4-(3-diethylaminopropylamino)pyrimido[4’,5’,4,5]thieno(2,3-b)quinoline (MDPTQ), a quinolone derivate that causes ROS-mediated apotosis in leukemia cell line. Toxicol Appl Pharmacol 222:80–88CrossRefPubMedGoogle Scholar
  32. Stiborová M, Sejbal J, Bořek-Dohalskґá L, Aimová D, Poljaková J, Forsterová K, Rupertová M, Wiesner J, Hudeček J, Wiessler M, Frei E (2004) The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N(2)-oxide. Cancer Res 64:8374–8380CrossRefPubMedGoogle Scholar
  33. Treat J, Greenspan A, Rahman A, McCabe MS, Byrne PJ (1989) Elliptinium: phase II study in advanced measurable breast cancer. Invest New Drugs 7:231–234CrossRefPubMedGoogle Scholar
  34. Vassal G, Merlin J-L, Terrier-Lacombe M-J, Grill J, Parker F, Sainte-Rose C, Aubert G, Morizet J, Sévenet N, Poullain M-G, Lucas C, Kalifa C (2003) In vivo antitumor activity of s16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts. Cancer Chemother Pharmacol 51:385–394PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesHealth Sciences University of HokkaidoIshikari-TobetsuJapan
  2. 2.Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical SciencesFukuyama UniversityHiroshimaJapan

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