Skip to main content
SpringerLink
Log in

Primary anti-proliferative activity evaluation of 1-(quinolizidin-1’-yl)methyl- and 1-(\(\omega \)-tert-amino)alkyl-substituted 2-phenyl-, 2-benzyl- and 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles on human cancer cell lines

  • Full-Length Paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Twenty benzimidazole derivatives bearing in position 1 a (\(\omega \)-tert-amino)alkyl chain (mainly quinolizidin-1-ylmethyl) and in position 2 an aromatic moiety (phenyl, benzyl or benzotriazol-1/2-ylmethyl) were evaluated at the National Cancer Institute (NCI) for anti-proliferative activity against a panel of 60 human cancer cell lines. Four compounds (6, 7, 9 and 10) displayed a large spectrum of activity with \(\text{ GI }_{50}<\) 10 \(\upmu \text{ M }\) on 24–57 cell lines, while thirteen compounds exhibited sub-micromolar or even nanomolar activity against single cell lines, such as leukemia CCRF-CEM, HL-60 and MOLT-4, CNS cancer SF-268 and, particularly, renal cancer UO-31, sometimes with outstanding selectivity (compounds 5-7, 11, 13 and 18).

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

Similar content being viewed by others

References

  1. Pagani F, Sparatore F (1965) Benzotriazolyl-alkyl-benzimidazoles and their dialkyl-aminoalkyl derivatives. Boll Chim Farm 104:427–431

    PubMed  CAS  Google Scholar 

  2. Sparatore F, Boido V, Fanelli F (1968) Dialkylaminoalkylbenzimidazoles of pharmacological interest. Farmaco Ed Sci 23:344–359

    CAS  Google Scholar 

  3. Paglietti G, Sparatore F (1972) Dialkylaminoalkylbenzimidazoles of pharmacological interest. III. Farmaco Ed Sci 27:333–342

    CAS  Google Scholar 

  4. Paglietti G, Boido V, Sparatore F (1975) Dialkylaminoalkylbenzimidazoles of pharmacological interest. IV. Farmaco Ed Sci 30:505–511

    CAS  Google Scholar 

  5. Boido A, Vazzana I, Sparatore F, Cenicola ML, Donnoli D, Marmo E (1991) Preparation and pharmacological activity of some 1-lupinylbenzimidazoles and 1-lupinylbenzotriazoles. Farmaco 46:775–788

    PubMed  CAS  Google Scholar 

  6. Sparatore F (1968) 2-Benzyl-1(1-quinolizidinylmethyl)-5-(trifluoromethyl)-benzimidazoles. US Pat 3394141 (July 23, 1968); Chem Abstr 69:86995

  7. Sun Q, Gatto B, Yu C, Liu A, Liu LF, LaVoie EJ (1994) Structure activity of topoisomerase I poisons related to Hoechst 33342. Bioorg Med Chem Lett 4:2871–2876. doi:10.1016/S0960-894X(01)80831-3

    Google Scholar 

  8. Sun Q, Gatto B, Yu C, Liu A, Liu LF, LaVoie EJ (1995) Synthesis and evaluation of terbenzimidazoles as topoisomerase I inhibitors. J Med Chem 38:3638–3644. doi:10.1021/jm00018a024

    Article  PubMed  CAS  Google Scholar 

  9. Kim JS, Gatto B, Yu C, Liu A, Liu LF, LaVoie EJ (1996) Substituted 2,5’-bi-1H-benzimidazoles: topoisomerase I inhibition and cytotoxicity. J Med Chem 39:992–998. doi:10.1021/jm950412w

    Article  PubMed  CAS  Google Scholar 

  10. Kim JS, Yu C, Liu A, Liu LF, LaVoie EJ (1997) Terbenzimidazoles: influence of 2”-, 4-, and 5-substituents on cytotoxicity and relative potency as topoisomerase I poisons. J Med Chem 40:2818–2824. doi:10.1021/jm960658g

    Article  PubMed  CAS  Google Scholar 

  11. Palmer BD, Smaill JB, Boyd M, Boschelli DH, Doherty AM, Hamby JM, Khatana SS, Kramer JB, Kraker AJ, Panek RL, Lu GH, Dahring TK, Winters RT, Showalter HDH, Denny WA (1998) Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor. J Med Chem 41:5457–5465. doi:10.1021/jm9804681

    Article  PubMed  CAS  Google Scholar 

  12. Palmer BD, Kraker AJ, Hartl BG, Panopoulos AD, Panek RL, Batley BL, Lu GH, Trumpp-Kallmeyer S, Showalter HDH, Denny WA (1999) Structure-activity relationships for 5-substituted 1-phenylbenzimidazoles as selective inhibitors of the platelet-derived growth factor receptor. J Med Chem 42:2373–2382. doi:10.1021/jm980658b

    Article  PubMed  CAS  Google Scholar 

  13. White AW, Almassy R, Calvert AH, Curtin NJ, Griffin RJ, Hostomsky Z, Maegley K, Newell DR, Srinivasan S, Golding BT (2000) Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase. J Med Chem 43:4084–4097. doi:10.1021/jm000950v

    Article  PubMed  CAS  Google Scholar 

  14. Xu YJ, Miao HQ, Pan W, Navarro EC, Tonra JR, Mitelman S, Camara MM, Deevi DS, Kiselyov AS, Kussie P, Wong WC, Liu H (2006) N-(4-[4-(1H-Benzoimidazol-2-yl)-arylamino]-methyl-phenyl)-benzamide derivatives as small molecule heparanase inhibitors. Bioorg Med Chem Lett 16:404–408. doi:10.1016/j.bmcl.2005.09.070

    Article  PubMed  CAS  Google Scholar 

  15. Pan W, Miao HQ, Xu YJ, Navarro EC, Tonra JR, Corcoran E, Lahiji A, Kussie P, Kiselyov AS, Wong WC, Liu H (2006) 1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors. Bioorg Med Chem Lett 16:409–412. doi:10.1016/j.bmcl.2005.09.069

    Article  PubMed  CAS  Google Scholar 

  16. Kim JS, Sun Q, Gatto B, Yu C, Liu A, Liu LF, LaVoie EJ (1996) Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons. Bioorg Med Chem 4:621–630. doi:10.1016/0968-0896(96)00047-8

    Article  PubMed  CAS  Google Scholar 

  17. Tonelli M, Paglietti G, Boido V, Sparatore F, Marongiu F, Marongiu E, La Colla P, Loddo R (2008) Antiviral activity of benzimidazole derivatives. I. Antiviral activity of 1-substituted-2-[(benzotriazol-1/2-yl)methyl]benzimidazoles. Chem Biodivers 5:2386–2401. doi:10.1002/cbdv.200890203

    Article  PubMed  CAS  Google Scholar 

  18. Tonelli M, Simone M, Tasso B, Novelli F, Boido V, Sparatore F, Paglietti G, Pricl S, Giliberti G, Blois S, Ibba C, Sanna G, Loddo R, La Colla P (2010) Antiviral activity of benzimidazole derivatives. II. Antiviral activity of 2-phenylbenzimidazole derivatives. Bioorg Med Chem 18:2937–2953. doi:10.1016/j.bmc.2010.02.037

    Article  PubMed  CAS  Google Scholar 

  19. Shoemaker RH (2006) The NCI 60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823. doi:10.1038/nrc1951

    Article  PubMed  CAS  Google Scholar 

  20. Boyd MR, Paull KD (1995) Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev Res 34:91–109. doi:10.1002/ddr.430340203

    Article  CAS  Google Scholar 

  21. Stinson SF, Alley MC, Kopp WC, Fiebig HH, Mullendore LA, Pittman AF, Kenney S, Keller J, Boyd MR (1992) Morphological and immunocytochemical characteristics of human tumor cell lines for use in a disease-oriented anticancer drug screen. Anticancer Res 12:1035–1053

    PubMed  CAS  Google Scholar 

  22. Akee RK, Ransom T, Ratnayake R, McMahon JB, Beutler JA (2012) Chlorinated englerins with selective inhibition of renal cancer cell growth. J Nat Prod 75:459–463. doi:10.1021/np200905u

    Article  PubMed  CAS  Google Scholar 

  23. Chan KP, Chen DYK (2011) Chemical synthesis and biological evaluation of the englerin analogues. ChemMedChem 6:420–423. doi:10.1002/cmdc.201000544

    Article  PubMed  CAS  Google Scholar 

  24. Ratnayake R, Covell D, Ransom TT, Gustafson KR, Beutler JA (2008) Englerin A, a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri. Org Letters 11:57–60. doi:10.1021/ol802339w

    Article  Google Scholar 

  25. Sulzmaier FJ, Li Z, Nakashige ML, Fash DM, Chain WJ, Ramos JW (2012) Englerin a selectively induces necrosis in human renal cancer cells. PLoS One 7:e48032. doi:10.1371/journal.pone.0048032

    Article  PubMed  CAS  Google Scholar 

  26. Barbieri F, Alama A, Tasso B, Boido V, Bruzzo C, Sparatore F (2003) Quinolizidinyl derivatives of iminodibenzyl and phenothiazine as multidrug resistance modulators in ovarian cancer cells. Invest New Drugs 21:413–420. doi:10.1023/A:1026295017158

    Article  PubMed  CAS  Google Scholar 

  27. Alama A, Tasso B, Novelli F, Sparatore F (2009) Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug Discov Today 14:500–508. doi:10.1016/j.drudis.2009.02.002

    Article  PubMed  CAS  Google Scholar 

  28. Sparatore A, Veronese M, Sparatore F (1987) Quinolizidine derivatives with antimicrobial activity. Farmaco Ed Sci 42:159–174

    CAS  Google Scholar 

  29. Sparatore A, Basilico N, Parapini S, Romeo S, Novelli F, Sparatore F, Taramelli D (2005) 4-Aminoquinoline quinolizidinyl- and quinolizidinylalkyl-derivatives with antimalarial activity. Bioorg Med Chem 13:5338–5345. doi:10.1016/j.bmc.2005.06.047

    Article  PubMed  CAS  Google Scholar 

  30. Sparatore A, Basilico N, Casagrande M, Parapini S, Taramelli D, Brun R, Wittlin S, Sparatore F (2008) Antimalarial activity of novel pyrrolizidinyl derivatives of 4-aminoquinoline. Bioorg Med Chem Lett 18:3737–3740. doi:10.1016/j.bmcl.2008.05.042

    Article  PubMed  CAS  Google Scholar 

  31. Tonelli M, Vettoretti G, Tasso B, Novelli F, Boido V, Sparatore F, Busonera B, Ouhtit A, Farci P, Blois S, Giliberti G, La Colla P (2011) Acridine derivatives as anti-BVDV agents. Antiviral Res 91:133–141. doi:10.1016/j.antiviral.2011.05.005

    Article  PubMed  CAS  Google Scholar 

  32. Villa V, Tonelli M, Thellung S, Corsaro A, Tasso B, Novelli F, Canu C, Pino A, Chiovitti K, Paludi D, Russo C, Sparatore A, Aceto A, Boido V, Sparatore F, Florio T (2011) Efficacy of novel acridine derivatives in the inhibition of hPrP90-231 prion protein fragment toxicity. Neurotox Res 19:556–574. doi:10.1007/s12640-010-9189-8

    Article  PubMed  CAS  Google Scholar 

  33. Kashfi K (2009) Anti-inflammatory agents as cancer therapeutics. Adv Pharmacol 57:31–89. doi:10.1016/S1054-3589(08)57002-5

    Article  PubMed  CAS  Google Scholar 

  34. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444. doi:10.1038/nature07205

    Article  PubMed  CAS  Google Scholar 

  35. Wang D, Dubois RN (2006) Prostaglandins and cancer. Gut 55:115–122. doi:10.1136/gut.2004.047100

    Google Scholar 

  36. Shriner RL, Land AH (1941) The structure of the bisulfite compound of acetaldehyde. J Org Chem 6:888–894. doi:10.1021/jo01206a014

    Article  CAS  Google Scholar 

  37. Mulliez M, Naudi C (1993) Synthèse d’\(\alpha \)-hydroxysulfinates. Tetrahedron. 2469–2473. doi:10.1016/S0040-4020(01)86325-0

  38. Geiger C, Zelenka C, Lehmkuhl K, Schepmann D, Englberger W, Wünsch B (2010) Conformationally constrained kappa receptor agonists: stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane derivatives. J Med Chem 53:4212–4222. doi:10.1021/jm100182p

    Google Scholar 

  39. She J, Jiang Z, Wang Y (2009) One-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines via cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with alkynes and p-tolylsulfonyl azide. Synlett:2023–2027. doi: 10.1055/s-0029-1217515

  40. Sparatore F, Boido V, Preziosi P, Miele E, De Natale G (1969) Synthesis and pharmacodynamic properties of some lupinane derivatives. Farmaco Ed Sci 24:587–621

    CAS  Google Scholar 

Download references

Acknowledgments

The Authors gratefully acknowledge the members of the National Cancer Institute Development Therapeutics Program (Bethesda, Maryland, USA) for performing the anti-cancer screening.

Author information

Authors and Affiliations

  1. Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 , Genoa, Italy

    Michele Tonelli, Bruno Tasso, Lorenzo Mina, Vito Boido & Fabio Sparatore

  2. Dipartimento di Chimica e Farmacia, Università di Sassari, Via Muroni 23a, 07100 , Sassari, Italy

    Giuseppe Paglietti

Authors
  1. Michele Tonelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Tasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lorenzo Mina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Paglietti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vito Boido
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabio Sparatore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michele Tonelli.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (doc 503 KB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tonelli, M., Tasso, B., Mina, L. et al. Primary anti-proliferative activity evaluation of 1-(quinolizidin-1’-yl)methyl- and 1-(\(\omega \)-tert-amino)alkyl-substituted 2-phenyl-, 2-benzyl- and 2-[(benzotriazol-1/2-yl)methyl]benzimidazoles on human cancer cell lines. Mol Divers 17, 409–419 (2013). https://doi.org/10.1007/s11030-013-9440-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-013-9440-3

Keywords

Search

Navigation