Skip to main content
SpringerLink
Log in

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

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2

Similar content being viewed by others

Abbreviations

IC50 :

Half maximal inhibitory concentration

MTT:

Thiazolyl blue tetrazolium bromide

WST-1:

Water-soluble tetrazolium salt-1

References

  • Alvarez M, Joule JA (2001) Ellipticine, uleine, apparicine, and related alkaloids. Alkaloids 57:235–273

    CAS  PubMed  Google Scholar 

  • Auclair C (1987) Multimodal action of antitumor agents on DNA: ellipticine series. Arch Biochem Biophys 259:1–14

    Article  CAS  PubMed  Google Scholar 

  • 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 61:1009–1012

    Article  Google Scholar 

  • 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 32:1037–1044

    Article  CAS  PubMed  Google Scholar 

  • 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 37:475–486

    Article  CAS  PubMed  Google Scholar 

  • 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 11:1334–1344

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Goodwin S, Smith AF, Horning EC (1959) Alkaloids of ochrosia elliptica labill. J Am Chem Soc 81:1903–1908

    Article  CAS  Google Scholar 

  • 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 119:198–205

    CAS  PubMed  Google Scholar 

  • 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 53:3186–3192

    CAS  PubMed  Google Scholar 

  • Gribble GW, Saulnier MG (1985) Syntheses of ellipticine and related pyridocarbazole alkaloids. Heterocycles 23:1277–1315

    Article  CAS  Google Scholar 

  • 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 13:175–184

    Article  CAS  PubMed  Google Scholar 

  • Hewlins MJ, Oliveria-Campos AM, Shannon PV (1984) Synthetic approaches to ellipticine derivatives and analogs of 6H-pyrido[4,3-b]carbazole. Synthesis 289–302

  • 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 56:193–207

    Article  CAS  Google Scholar 

  • Ishikura M, Takahashi N, Yamada K, Abe T, Yanada R (2008) Formal synthesis of olivacine via indolylborate. Helv Chim Acta 91(10):1828–1837

    Article  CAS  Google Scholar 

  • 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 41:1118–1122

    Article  CAS  Google Scholar 

  • 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 2290–2299

  • Kansal VK, Potier P (1986) Biogenetic, synthetic and biochemical aspects of ellipticine, an antitumor alkaloid. Tetrahedron 42:2389–2408

    Article  CAS  Google Scholar 

  • 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 30:226–228

    Article  CAS  PubMed  Google Scholar 

  • Knölker H-J, Reddy KR (2002) Isolation and synthesis of biologically active carbazole alkaloids. Chem Rev 102:4303–4428

    Article  PubMed  Google Scholar 

  • Kohn KW, Waring MJ, Glaubiger D, Friedman CA (1975) Intercalative binding of ellipticine to DNA. Cancer Res 35:71–76

    CAS  PubMed  Google Scholar 

  • 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 50:95–103

    Article  CAS  PubMed  Google Scholar 

  • Miller CM, McCarthy FO (2012) Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles. RSC Adv 2:8883–8918

    Article  CAS  Google Scholar 

  • 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 266:1820–1829

    CAS  PubMed  Google Scholar 

  • 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 24:2631–2634

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • O’Sullivan EC, Miller CM, Dean FM, McCarthy FO (2013) Emerging targets in the bioactivity of ellipticine and derivatives. Stud Nat Prod Chem 39:189–232

    Article  Google Scholar 

  • Sainsbury M (1977) The synthesis of 6H-pyrido[4,3-b]carbazoles. Synthesis 437–448

  • Schmutz J, Hunzicker F (1958) Alkaloids of Aspidosperma Olivaceum. Pharm Acta Helv 33:341–347

    CAS  PubMed  Google Scholar 

  • 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 222:80–88

    Article  CAS  PubMed  Google Scholar 

  • 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 64:8374–8380

    Article  PubMed  Google Scholar 

  • Treat J, Greenspan A, Rahman A, McCabe MS, Byrne PJ (1989) Elliptinium: phase II study in advanced measurable breast cancer. Invest New Drugs 7:231–234

    Article  CAS  PubMed  Google Scholar 

  • 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 51:385–394

    CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan

    Tomoki Itoh, Noriyuki Hatae, Teruki Yoshimura & Minoru Ishikura

  2. Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, 729-0292, Japan

    Takashi Nishiyama, Tominari Choshi & Satoshi Hibino

Authors
  1. Tomoki Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noriyuki Hatae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tominari Choshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Hibino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teruki Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Minoru Ishikura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minoru Ishikura.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Itoh, T., Hatae, N., Nishiyama, T. et al. Synthesis and cytotoxicity of pyrido[4,3-b]carbazole alkaloids against HCT-116 and HL-60 cells. Med Chem Res 27, 412–419 (2018). https://doi.org/10.1007/s00044-017-2068-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-017-2068-6

Keywords

Search

Navigation