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Synthesis of tetrahydropyrazolo-quinazoline and tetrahydropyrazolo-pyrimidocarbazole derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors

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Abstract

The multi-component reactions of arylhydrazopyrazoles 2, aromatic aldehydes 3 and cylohexane-1,3-dione gave pyrazoloquinazolinones 5. In addition, compounds 5 reacted with elemental sulfur and either of malononitrile or ethyl cyanoacetate to give the thiophene derivatives 7, respectively. Compounds 5 were used to synthesis the 5,6,11,12-tetrahydro-3H-pyrazolo[1’,5’:1,2]pyrimido[5,4-a]carbazol-2-ol derivatives 9 through their reaction with phenylhydrazine. Similarly, the reaction of the pyrazole derivatives 2, with 3 and dimedone (10) gave the quinoline derivatives 11. The newly synthesized products were evaluated against c-Met kinase, PC-3 prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds were 5b, 5c, 5e–i, 7e, 7p, 7q, 7r, and 11i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Some compounds were selected to examine their Pim-1 kinase inhibition activity where compounds 5h and 7u showed high inhibitions.

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References

  • Bandini M, Eichholzer A (2009) Catalytic functionalization of indoles in a new dimension. Angew Chem Int Ed 48:9808–9844

    Google Scholar 

  • Berger DM, Dutia M, Powell D, Floyd MB, Torres N, Mallon R, Wojciechowicz D, Kim S, Feldberg L, Collins K, Chaudhary I (2008) 4-Anilino-7-alkenylquinoline-3-carbonitriles as potent MEK1 kinase inhibitors. Bioorg Med Chem 16:9202–9211

    Article  CAS  PubMed  Google Scholar 

  • Berger D, Dutia M, Powell D, Wu B, Wissner A, Boschelli DH, Floyd MB, Zhang N, Torres N, Levin J, Du X, Wojciehowicz D, Discafani C, Kohler C, Kim SC, Feldberg LR, Collins K, Mallon R (2003) Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. Bioorg. Med Chem Lett 13:3031–3034

    Article  CAS  PubMed  Google Scholar 

  • Bergstrom FW (1944) Skraup quinoline synthesis. Chem Rev 35:152–153

    Article  Google Scholar 

  • Charpentier P, Lobregat V, Levacher V, Dupas G, Queguiner G, Bourguignon J (1998) An Efficient Synthesis of 3-cyanoquinoline derivatives. Tetrahedron Lett 39:4013–4016

    Article  CAS  Google Scholar 

  • Cheng CC, Yan SJ (1982) The Friedländer synthesis of quinolines. Org React 28:37–201

    CAS  Google Scholar 

  • Cui SL, Wang J, Wang YG (2008) Synthesis of Indoles via domino reaction of N-Aryl amides and ethyl diazoacetate. J Am Chem Soc 130:13526–13527

    Article  CAS  PubMed  Google Scholar 

  • Elnagdi EM, Hassen NH, Abdel-Maksoud FA, Abdel-Motaleb RM, Maawad RA, Mahmoud FF (1989) Studies on condensed pyrazoles: synthesis of new methyl- and aminopyrazolo[1,5-a]pyrimidines and of pyrazolo[5,1-c][1,2,4]triazines. Coll of Czach Chem Comm 54:1082–1091

    Article  CAS  Google Scholar 

  • Fischer E, Hess O (1984) Synthesis of indole derivatives. Ber Dtsch Chem Ges 17:559–568

    Article  Google Scholar 

  • Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC (2010) Nitrile-containing pharmaceuticals: Efficacious roles of the nitrile pharmacophore. J Med Chem 53:7902–7917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones G (1977) Taylor EC (ed) The chemistry of heterocyclic compounds Chromenes, Chromanones and Chromones. Vol. 32, Wiley, London, pp 93–380

  • Li K, Li Y, Zhou D, Fan Y, Guo H, Ma T, Wen J, Liu D, Zhao L (2016) Synthesis and biological evaluation of quinoline derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors. Bioorg Med Chem 24:1889–1897

    Article  CAS  PubMed  Google Scholar 

  • Li S, Zhao Y, Wang K, Gao Y, Han J, Cui B, Gong P (2013) Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 21:2843–2855

    Article  CAS  PubMed  Google Scholar 

  • Liao W, Xu C, Ji X, Hu G, Ren L, Liu Y, Li R, Gong P, Sun T (2014) Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors. Eur J Med Chem 87:508–518

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Nie M, Wang Y, Hu J, Zhang F, Gao Y, Liu Y, Gong P (2016) Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. Eur J Med Chem 123:431–446

    Article  CAS  PubMed  Google Scholar 

  • Manske HF, Kukla M (1953) The skraup synthesis of quinolines. Org React 7:59–98

    Google Scholar 

  • Martine S, Evelenya K, Macher JP, Jean-Jacques B, Abarghaz M, Wagner P, Ronsin G (2006) US patent 183909, A1

  • Mohareb RM, Abdo NY (2015) Synthesis and cytotoxic evaluation of pyran, dihydropyridine and thiophene derivatives of 3-acetylcoumarin. Chem Pharm Bull 63:678–687

    Article  CAS  PubMed  Google Scholar 

  • Mohareb RM, El-Omran F, Azam RA (2014) Heterocyclic ring extension of estrone: Synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives. Steroids 84:46–45

    Article  CAS  PubMed  Google Scholar 

  • Muscia GC, Bollini M, Carnevale JP, Bruno AM, Asis SE (2006) Microwave-assisted Friedländer synthesis of quinolines derivatives as potential antiparasitic agents. Tetrahedron Lett 47:8811–8815

    Article  CAS  Google Scholar 

  • Ökten S, Çakmak O (2015) Synthesis of novel cyano quinoline derivatives. Tetrahedron Lett 56:5337–5340

    Article  Google Scholar 

  • Park IK, Suh SE, Lim BY, Cho CG (2009) Aryl hydrazide beyond as surrogate of aryl hydrazine in the Fischer indolization: the synthesis of N-Cbz-indoles, N-Cbz-carbazoles, and N,N′-Bis-Cbz-pyrrolo[2,3-f]indoles. Org Lett 11:5454–5456

    Article  CAS  PubMed  Google Scholar 

  • Pauvert M, Collet SC, Bertrand AMJ, Guingant AY, Evain M (2005) Synthesis of chiral N-protected 1,2-dihydro-quinoline-2-carbonitrile and 1,2-dihydro-isoquinoline-1-carbonitrile via an asymmetric Reissert reaction. Tetrahedron Lett 46:2983–2987

    Article  CAS  Google Scholar 

  • Solomon VR, Lee H (2009) Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 625:220–233

    Article  CAS  PubMed  Google Scholar 

  • Srivastava SK, Chauhan PMS, Bhaduri AP, Fatima N, Chatterjee RJ (2000) Quinolones:  Novel probes in antifilarial chemotheraphy. Med Chem 43:2275–2279

    Article  CAS  Google Scholar 

  • Tang Q, Wang L, Tu Y, Zhu W, Luo R, Tu Q, Wang P, Wu C, Gong P, Zheng P (2016) Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors. Bioorg Med Chem Lettt 26:1680–1684

    Article  CAS  Google Scholar 

  • Tang Q, Zhang G, Du X, Zhu W, Li R, Li R, Lin H, Li P, Cheng M, Gong P, Zhao Y (2014) Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors. Bioorg Med Chem 22:1236–1249

    Article  CAS  PubMed  Google Scholar 

  • Tang Q, Zhao Y, Du X, Chong L, Gong P, Guo C (2013) Design, synthesis, and structureeactivity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents. Eur J Med Chem 69:77–89

    Article  CAS  PubMed  Google Scholar 

  • Wissner A, Johnson BD, Reich MF, Floyd MB, Kitchen DB, Tsou HR (1999) Substituted 3-Cyano Quinolines. US Patent 1999-6002008 filled Apr 3, 1997, issued Dec 14, 1999

  • Zhang N, Wu B, Eudy N, Wang Y, Ye F, Powell D, Wissner A, Feldberg LR, Kim SC, Mallon R, Kovacs ED, Toral-Barza L, Kohler CA (2001) MEK (MAPKK) inhibitors. Part 2: Structure–activity relationships of 4-anilino-3-cyano-6,7-dialkoxyquinolines. Bioorg Med Chem Lett 11:1407–1410

    Article  CAS  PubMed  Google Scholar 

  • Zhang N, Wu B, Powell D, Wissner A, Floyd MB, Kovacs ED, Toral- Barza L, Kohler C (2000) Synthesis and structure–activity relationships of 3-cyano-4-(phenoxyanilino)quinolines as MEK (MAPKK) inhibitors. Bioorg Med Chem Lett 10:2825–2828

    Article  CAS  PubMed  Google Scholar 

  • Zhou S, Liao H, Liu M, Feng G, Fu B, Li R, Cheng M (2014) Discovery and biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 22:6438–6452

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

RMM would like to thank the Alexander von Humboldt Foundation in Bonn, Germany for affording him regular fellowships in Germany for finance and completing his research work.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of science, Cairo University, Giza, Arab Republic of Egypt

    Rafat M. Mohareb

  2. Department of Chemistry, Faculty of Science, Helwan University, Cairo, Arab Republic of Egypt

    Nermeen S. Abbas

  3. Department of Chemistry, Faculty of Science, Taibah University, Medina, Saudi Arabia

    Nermeen S. Abbas

  4. National Organization for Research & Control of Biologicals, Giza, Arab Republic of Egypt

    Abeer A. Mohamed

Authors
  1. Rafat M. Mohareb
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  2. Nermeen S. Abbas
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  3. Abeer A. Mohamed
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Correspondence to Rafat M. Mohareb.

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Mohareb, R.M., Abbas, N.S. & Mohamed, A.A. Synthesis of tetrahydropyrazolo-quinazoline and tetrahydropyrazolo-pyrimidocarbazole derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors. Med Chem Res 26, 1073–1088 (2017). https://doi.org/10.1007/s00044-017-1811-3

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  • DOI: https://doi.org/10.1007/s00044-017-1811-3

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