Skip to main content
SpringerLink
Log in

Antiproliferative activity of naphthoquinones and indane carboxylic acids from lapachol against a panel of human cancer cell lines

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

Abstract

Lapachol (1) is a well-studied natural product isolated from plants of the Bignoniaceae family and demonstrates diverse biological effects. Historically, chemical transformation of the lapachol scaffold has yielded new derivatives with impressive biological activity and rich chemical diversity. β-lapachone (2), α-lapachone (3), and 2-acetylfuronaphthoquinone (4) are examples of analogs derived from lapachol that show superior antitumor activity compared with the natural product. In the present study, novel indane carboxylic acid: 2,2-dimethyl-2,3-dihydroindeno[1,2-b]pyran-4,5-dione (9) and methyl 5-hydroxy-2,2-dimethyl-2,3,4,5-tetrahydroindeno[1,2-b]pyran-5-carboxylate (10) and naphthoquinone derivatives were synthesized from lapachol with structural similarities to the antitumor lapachol derivatives. The synthesized compounds were evaluated for antiproliferative activities against a panel of human cancer cell lines including in vitro models for neuroblastoma, melanoma, glioblastoma, and non-small cell lung cancer. As expected, the most potent derivatives were those incorporating β-naphthoquinone and α-naphthoquinono[2,3-b]furan skeletons. Many of these compounds possessed nanomolar to single digit micromolar antiproliferative potency. However, the most interesting analog evaluated was the dione 9 with an indeno[1,2-b]pyran skeleton, which demonstrated potent cytotoxic activity. The current investigation identified several new lead compounds that could be used as starting points for anticancer drug discovery.

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
Scheme 1
Fig. 2

Similar content being viewed by others

References

  • Aksenov AV, Smirnov AN, Magedov IV, Reisenauer MR, Aksenov NA, Aksenova IV, Pendleton AL, Nguyen G, Johnston RK, Rubin M, De Carvalho A, Kiss R, Mathieu V, Lefranc F, Correa J, Cavazos DA, Brenner AJ, Bryan BA, Rogelj S, Kornienko A, Frolova LV (2015) Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates against drug-resistant cancer cells. J Med Chem 58(5):2206–2220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amann VC, Ramelyte E, Thurneysen S, Pitocco R, Bentele-Jaberg N, Goldinger SM, Dummer R, Mangana J (2017) Developments in targeted therapy in melanoma. Eur J Surg Oncol 43(3):581–593

    Article  CAS  PubMed  Google Scholar 

  • Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ (2000) Role of quinones in toxicology. Chem Res Toxicol 13(3):135–160

    Article  CAS  PubMed  Google Scholar 

  • Castellanos JRG, Prieto JM, Heinrich M (2009) Red Lapacho (Tabebuia impetiginosa)—a global ethnopharmacological comomodity? J Ethnopharmacol 121:1–13

    Article  Google Scholar 

  • Dahlin JL, Nissink JWM, Strasser JM, Francis S, Higgins LA, Zhou H, Zhang Z, Walters MA (2015) PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J Med Chem 58(5):2091–2113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dasari R, De Carvalho A, Medellin DC, Middleton KN, Hague F, Volmar MNM, Frolova LV, Rossato MF, De La Chapa JJ, Dybdal-Hargreaves NF, Pillai A, Kälin RE, Mathieu V, Rogelj S, Gonzales CB, Calixto JB, Evidente A, Gautier M, Munirathinam G, Glass R, Burth P, Pelly SC, Van Otterlo WA, Kiss R, Kornienko A (2015) Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines. Eur J Med Chem 103:226–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva Jr EN, de Souza MCBV, Pinto AV, Pinto MCFR, Goulart MOF, Barros FWA, Pessoa C, Costa-Lotufo LV, Montenegro RC, de Moraes MO, Ferreira VF (2007) Synthesis and potent antitumor activity of new arylamino derivatives of nor-beta-lapachone and nor-alpha-lapachone. Bioorg Med Chem 15:7035–7041

    Article  Google Scholar 

  • Esposito MR, Aveic S, Seydel A, Tonini GP (2017) Neuroblastoma treatment in the post-genomic era. J Biomed Sci 24(1):14

    Article  PubMed  PubMed Central  Google Scholar 

  • Eyong KO, Krohn K, Hussain H, Folefoc GN, Nkengfack AE, Schulz B, Hu Q (2005) Newbouldiaquinone and newbouldiamide: a new naphthoquinone– anthraquinone coupled pigment and a new ceramide from Newbouldia laevis. Chem Pharm Bull 53(6):616–619

    Article  CAS  PubMed  Google Scholar 

  • Eyong KO, Folefoc GN, Kuete V, Beng VP, Hussain H, Krohn K, Nkengfack AE, Saeftel M, Sarite SR, Achim H (2006) Newbouldiaquinone A: a naphthoquinone-anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from Newbouldia laevis. Phytochemistry 67:605–609

    Article  CAS  PubMed  Google Scholar 

  • Eyong KO, Kumar SM, Folefoc GN, Nkengfack AE, Baskaran S (2008) Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol. Bioorg Med Chem Lett 18:5387–5390

    Article  CAS  PubMed  Google Scholar 

  • Eyong KO, Puppala M, Kumar PM, Lamshöft M, Folefoc GN, Spiteller M, Baskaran S (2013) A mechanistic study on the Hooker oxidation: synthesis of novel indane carboxylic acid derivatives from lapachol. Org Biomol Chem 11:459–468

    Article  CAS  PubMed  Google Scholar 

  • Eyong KO, Chinthapally K, SenthilKumar S, Lamshöft M, Folefoc GN, Baskaran S (2015a) Conversion of lapachol to lomatiol: synthesis of novel naphthoquinone derivatives. New J Chem 39:9611–9616

    Article  CAS  Google Scholar 

  • Eyong KO, Ketsemen LH, Ghansenyuy YS, Folefoc NG (2015b) Chemical constituents, the stereochemistry of 3-hydroxy furonaphthoquinones from the root bark of Newbouldia laevis Seem (Bignoniaceae), and screening against Onchocerca ochengi parasites. Med Chem Res 24:965–969

    Article  CAS  Google Scholar 

  • Fiorito S, Epifano F, Bruyère C, Mathieu V, Kiss R, Genovese S (2014) Growth inhibitory activity for cancer cell lines of lapachol and its natural and semi-synthetic derivatives. Bioorg Med Chem Lett 24:454–457

    Article  CAS  PubMed  Google Scholar 

  • Habtemariam S (2010) Knipholone anthrone from Kniphofia foliosa induces a rapid onset of necrotic cell death in cancer cells. Fitoterapia 81(8):1013–1019

    Article  CAS  PubMed  Google Scholar 

  • Hussain H, Krohn K, Ahmad VU, Miana GA, Green IR (2007) Lapachol: an overview. Arkivoc 2:145–171

    Google Scholar 

  • Induli M, Gebru M, Abdissa N, Akala H, Wekesa I, Byamukama R, Heydenreic M, Murunga S, Dagne E, Yenesew A (2013) Antiplasmodial quinones from the rhizomes of Kniphofia foliosa. Nat Prod Commun 8(9):1261–1264

    CAS  PubMed  Google Scholar 

  • Kuete V, Eyong KO, Folefoc NG, Beng VP, Hussain H, Krohn K, Nkengfack AE (2007) Antimicrobial activity of the methanolic extract and of the chemical constituents isolated from Newbouldia laevis. Pharmazie 62:552–556

    CAS  PubMed  Google Scholar 

  • Kornienko A, Mathieu V, Rastogi SK, Lefranc F, Kiss R (2013) Therapeutic agents triggering nonapoptotic cancer cell death. J Med Chem 56(12):4823–4839

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Li CJ, Yu D, Pardee AB (2000) Potent induction of apoptosis by beta-lapachone in human multiple myeloma cell lines and patient cells. Mol Med 6(12):1008–1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim SM, Jeong Y, Lee S, Im H, Tae HS, Kim BG, Park HD, Park J, Hong S (2015) Identification of β-Lapachone analogs as Novel MALT1 inhibitors to treat an aggressive subtype of diffuse large B-cell lymphoma. J Med Chem 58:8491–8502

    Article  CAS  PubMed  Google Scholar 

  • Monks TJ, Hanzlik RP, Cohen GM, Ross D, Graham DG (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112(1):2–16

    Article  CAS  PubMed  Google Scholar 

  • Nepomuceno JC (2011) Lapachol and its derivatives as potential drugs for cancer treatment. iConcept Press, Brazil

  • Oliveira MF, Lemos TLG, Mattos MCD, Segundo TA, Santiago GMP, Braz-Filho R (2002) New enamine derivatives of lapachol and biological activity. An da Academia Brasileira de Ciências 74:211–221

    Article  CAS  Google Scholar 

  • Osuka S, Van Meir EG (2017) Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest 127(2):415–426

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez-Sacau E, Dıaz-Penate RG, Estevez-Braun A, Ravelo AG, Garcıa-Castellano JM, Pardo L, Campillo M (2007) Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line. J Med Chem 50:696–706

    Article  CAS  PubMed  Google Scholar 

  • Queiroz MLS, Valadares MC, Torello CO, Ramos AL, Oliveira AB, Rocha FD, Arruda VA, Accorei WR (2008) Comparative studies of the effects of Tabebuia avellanedae bark extract and beta-lapachone on the hematopoietic response of tumour-bearing mice. J Ethnopharmacol 117:228–235

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Perez C, Lorenzo-Castrillejo I, Quevedo O, Garcia-Luis J, Matos-Perdomo E, Medina-Coello C, Estevez-Braun A, Machin F (2014) Yeast cytotoxic sensitivity to the antitumour agent β-lapachone depends mainly on oxidative stress and is largely independent of microtubule- or topoisomerase- mediated DNA damage. Biochemical Pharmacol 92:206–219

    Article  CAS  Google Scholar 

  • Rios-Luci C, Bonifazi EL, Leon LG, Montero JC, Burton G, Pandiella A, Misico RI, Padron JM (2012) β-Lapachone analogs with enhanced antiproliferative activity. Eur J Medicinal Chem 53:264–274

    Article  CAS  Google Scholar 

  • Rossi A, Sacco PC, Santabarbara G, Sgambato A, Casaluce F, Palazzolo G, Maione P, Gridelli C (2017) Developments in pharmacotherapy for treating metastatic non-small cell lung cancer. Expert Opin Pharmacother 18(2):151–163

    Article  CAS  PubMed  Google Scholar 

  • Souza-Silva F, Nascimento SB, Bourguignon SC, Pereira BA, Carneiro PF, Da Silva WS, Alves CR, De Pinho RT (2014) Evidences for leishmanicidal activity of the naphthoquinone derivative epoxy-α-lapachone. Exp Parasitol 147:81–84

    Article  CAS  PubMed  Google Scholar 

  • Sunassee SN, Veale CGL, Shunmoogam-Gounden N, Osoniyi O, Hendricks DT, Caira MR, de la Mare J-A, Edkins AL, Pinto AV, da Silva Jr EN, Davies-Coleman MT (2013) Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-napthoquinones against oesophageal cancer cells. Eur J Med Chem 62:98–110

    Article  CAS  PubMed  Google Scholar 

  • Tanis SP, Chuang YH, Head DB (1988) Furans in synthesis. 8. Formal total syntheses of (.+-.)- and (+)-aphidicolin. J Org Chem 53:4929–4938

  • Ueda S (2005) The present invention relates to a novel compound possessing antitumor activity, and an antitumor agent comprising said compounds. US Patent 5663197

  • Yamashita M, Kaneko M, Iida A, Tokuda H, Nishimura K (2007) Stereoselective synthesis and cytotoxicity of a cancer chemopreventive naphthoquinone from Tabebuia avellanedae. Bioorg Med Chem Lett 17(23):6417–6420

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, Ma X, Sung D, Li M, Kosti A, Lin G, Chen Y, Pertsemlidis A, Th H, Du L (2015) microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest. RNA Biol 12(5):538–554

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao Z, Ma X, Shelton SD, Sung DC, Li M, Hernandez D, Zhang M, Losiewicz MD, Chen Y, Pertsemlidis A, Yu X, Liu Y, Du L (2016) A combined gene expression and functional study reveals the crosstalk between N-Myc and differentiation-inducing microRNAs in neuroblastoma cells. Oncotarget 7:79372–79387

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the council for International Exchange of Scholars (CIES) for the J. William Fulbright Visiting Scholar program to Pr Kenneth Eyong. The Molecular Bioscience Center, the CPRIT Synthesis and Drug-Lead Discovery Laboratory and the Departments of Chemistry/Biochemistry and Biology at Baylor University, and Baylor University and Texas State University, San Marcos for infrastructure and financial support. The University of Yaounde I and the Government of Cameroon for financial support through the Fonds d’Appuis a la Recherche.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry and the CPRIT Synthesis and Drug-Lead Discovery Laboratory, Baylor University, Waco, TX, 76798, USA

    Kenneth O. Eyong, Kenneth G. Hull & Daniel Romo

  2. Department of Organic Chemistry, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon

    Kenneth O. Eyong, Herve L. Ketsemen & Gabriel N. Folefoc

  3. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA

    Zhenze Zhao, Liqin Du & Alexander Kornienko

  4. Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium

    Aude Ingels & Veronique Mathieu

  5. Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol, 355009, Russian Federation

    Alexander Kornienko

  6. Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036, India

    Sundarababu Baskaran

Authors
  1. Kenneth O. Eyong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Herve L. Ketsemen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenze Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liqin Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aude Ingels
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Veronique Mathieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexander Kornienko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenneth G. Hull
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gabriel N. Folefoc
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sundarababu Baskaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel Romo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth O. Eyong.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eyong, K.O., Ketsemen, H.L., Zhao, Z. et al. Antiproliferative activity of naphthoquinones and indane carboxylic acids from lapachol against a panel of human cancer cell lines. Med Chem Res 29, 1058–1066 (2020). https://doi.org/10.1007/s00044-020-02545-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-020-02545-0

Keywords

Search

Navigation