Medicinal Chemistry Research

, Volume 27, Issue 2, pp 442–457 | Cite as

1,4-Disubstituted-5-hydroxy-3-methylpyrazoles and some derived ring systems as cytotoxic and DNA binding agents. Synthesis, in vitro biological evaluation and in silico ADME study

Original Research
  • 60 Downloads

Abstract

Some novel polysubstituted pyrazoles, bipyrazoles and pyranopyrazoles, supported with various chemotherapeutically-active pharmacophores, were synthesized and biologically evaluated for their cytotoxic potential. Fifteen compounds (79, 12, 16, 17, 19, 21, 22, 26, 28, 30, 32, 33, and 34) exhibited variable degrees of cytotoxic activity against a panel of three cancer cell lines, among which the analogs 16, 17, 21, 26, and 34 showed a considerable broad spectrum cytotoxic potential, with special effectiveness against the colon HT29 and breast MCF7 cancer cell lines. In particular, compounds 16, 17, and 26 displayed double the activity of doxorubicin against colon carcinoma HT29 cell line, while the pyranopyrazole analog 34 was nearly equiactive with the reference cytotoxic agent. Meanwhile, the analogs 16 and 17 were nearly equipotent to doxorubicin against breast MCF7 cell line. DNA-binding activities of the most active compounds were in agreement with the obtained anticancer activity, where compounds 16, 17, 26, and 34 displayed the highest affinity. In silico calculations of molecular properties revealed that most of the active compounds comply with Lipinski’s RO5 and Veber’s criteria for good bioavailability suggesting good drug-likeness properties upon oral administration.

Keywords

Synthesis Pyrazoles Bipyrazoles Cytotoxicity DNA binding Molecular properties 

Notes

Acknowledgements

The authors are very grateful to the staff members of the Bioassay-Cell Culture laboratory, in vitro bioassays on human tumor cell lines for drug discovery unit, National Research Center (NRC), Cairo, Egypt, for their efforts in performing the MTT cytotoxicity assay.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT (2004) Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett 14:217–223CrossRefPubMedGoogle Scholar
  2. Ait‐Baziz N, Rachedi Y, Silva AMS (2010) Reactivity of some structural analogs of dehydroacetic acid with o-phenylenediamine. Arkivoc 10:86–97Google Scholar
  3. Al-Said MS, Ghorab MM, Al-Qasoumi SI, El-Hossary EM, Noaman E (2010) Synthesis and in vitro anticancer screening of some novel 4-[2-amino-3-cyano-4-substituted-5,6,7,8-tetrahydroquinolin-1-(4H)-yl]benzenesulfonamides. Eur J Med Chem 45:3011–3018CrossRefPubMedGoogle Scholar
  4. Arcangeli A, Crociani O, Lastraioli E, Masi A, Pillozzi S, Becchetti A (2009) Targeting ion channels in cancer: a novel frontier in antineoplastic therapy. Curr Med Chem 16:66–93CrossRefPubMedGoogle Scholar
  5. Ashour FA, Rida SM, El-Hawash SAM, ElSemary MM, Badr MH (2011) Synthesis, anticancer, anti-HIV-1, and antimicrobial activity of some tricyclic triazino and triazolo[4,3-e]purine derivatives. Med Chem Res 21:1107–1119CrossRefGoogle Scholar
  6. Barton JK (1986) Metals and DNA: molecular left-handed complements. Science 233:727–734CrossRefPubMedGoogle Scholar
  7. Benaamane N, Nedjar-Kolli B, Bentarzi Y, Hammal L, Geronikaki A, Eleftherioub P, Lagunin A (2008) Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems. Bioorg Med Chem 16:3059–3066CrossRefPubMedGoogle Scholar
  8. Bendaas A, Hamdi M, Sellier N (1999) Synthesis of bipyrazoles and pyrazoloisoxazoles from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one. J Heterocyclic Chem 36:1291–1294CrossRefGoogle Scholar
  9. Bhavanarushi S, Kanakaiah V, Yakaiah E, Saddanapu V, Addlagatta A, Rani JV (2013) Synthesis, cytotoxic, and DNA binding studies of novel fluorinated condensed pyrano pyrazoles. Med Chem Res 22:2446–2454CrossRefGoogle Scholar
  10. Burres NS, Frigo A, Rasmussen RR, McAlpine JB (1992) A colorimetric microassay for the detection of agents that interact with DNA. J Nat Prod 55:1582–1587CrossRefPubMedGoogle Scholar
  11. Cankara Pirol S, Calıskan B, Durmaz I, Atalay R, Banoglu E (2014) Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines. Eur J Med Chem 87:140–149CrossRefPubMedGoogle Scholar
  12. Cantos A, de March P, Moreno-Manas M, Pla A, Sanchez-Ferrando F, Virgili A (1987) Synthesis of pyrano[4,3-c]pyrazol-4(1H)-ones and -4(2H)-ones from dehydroacetic acid. Homo- and heteronuclear selective noe measurements for unambiguous structure assignment. B Chem Soc Japan 60:4425–4431CrossRefGoogle Scholar
  13. Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502CrossRefPubMedGoogle Scholar
  14. Chatterjee R, Mitra A (2015) An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer. Int Immunopharmacol 24:335–345CrossRefPubMedGoogle Scholar
  15. Chobe SS, Dawane BS, Tumbi KM, Nandekar PP, Sangamwar AT (2012) An ecofriendly synthesis and DNA binding interaction study of some pyrazolo[1,5-a]pyrimidines derivatives. Bioorg Med Chem Lett 22:7566–7572CrossRefPubMedGoogle Scholar
  16. Denizot F, Lang R (1986) Rapid colourimetric assay for cellular growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 22:271–277CrossRefGoogle Scholar
  17. Faidallah HM, Rostom SAF, Badr MH, Ismail AE, El Mohamadi AM (2015) Synthesis of some 1,4,6-trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles and their biological evaluation as cytotoxic and antimicrobial agents. Arch Pharm Chem Life Sci 348:824–834CrossRefGoogle Scholar
  18. Gamal El-Din MM, El-Gamal MI, Abdel-Maksoud MS, Yoo KH, Oh CH (2015) Synthesis and broad-spectrum antiproliferative activity of diarylamides and diarylureas possessing 1,3,4-oxadiazole derivatives. Bioorg Med Chem Lett 25:1692–1699CrossRefPubMedGoogle Scholar
  19. Gao J, Chen M, Tong X, Zhu H, Yan H, Liu D, Li W, Qi S, Xiao D, Wang Y, Lu Y, Jiang F (2015) Synthesis, antitumor activity, and structure-activity relationship of some benzo[a]pyrano[2,3-c]phenazine derivatives. Comb Chem High Throughput Screen 18:960–974CrossRefPubMedGoogle Scholar
  20. Gelin S, Chantegrel B, Nadi AI (1983) Synthesis of 4-(acylacetyl)-1-phenyl-2-pyrazolin-5-ones from 3-acyl-2H-pyran-2,4(3H)-diones. Their synthetic applications to functionalized 4-oxopyrano[2,3-c]pyrazole derivatives. J Org Chem 48:4078–4082CrossRefGoogle Scholar
  21. Geuther A (1866) Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer. Wissenschaften Zeitschrift Chem 303–308Google Scholar
  22. Ghorab MM, Ragab FA, Heiba HI, Youssef HA, El-Gazzar MG (2012) Synthesis of novel pyrazole and pyrimidine derivatives bearing sulfonamide moiety as antitumor and radiosensitizing agents. Med Chem Res 21:1376–1383CrossRefGoogle Scholar
  23. Hurley LH (2002) DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2:188–200CrossRefPubMedGoogle Scholar
  24. Kibria G, Hatakeyama H, Harashima H (2014) Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res 37:4–15CrossRefPubMedGoogle Scholar
  25. Lipinski CA, Lombardo L, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26CrossRefPubMedGoogle Scholar
  26. Luo Y, Zhou Y, Fu J, Zhu HL (2014) 4, 5-Dihydropyrazole derivatives containing oxygen-bearing heterocycles as potential telomerase inhibitors with anticancer activity. RSC Adv 4:23904–23913CrossRefGoogle Scholar
  27. Manetti F, Brullo C, Magnani M, Mosci F, Chelli B, Crespan E, Schenone S, Naldini A, Bruno O, Trincavelli ML (2008) Structure-based optimization of pyrazolo[3,4-d] pyrimidines as abl inhibitors and antiproliferative agents toward human leukemia cell lines. J Med Chem 51:1252–1259CrossRefPubMedGoogle Scholar
  28. Martinez R, Chacon-Garcia L (2005) The search for DNA-intercalators as antitumoral drugs; what worked and what did not work. Curr Med Chem 12:127–151CrossRefPubMedGoogle Scholar
  29. Mishra N, Poonia K, Kumar D (2013) An overview of biological aspects of Schiff base metal complexes. Int J Adv Sci Technol 2:52–66Google Scholar
  30. Molinspiration Chemoinformatics (2014) Brastislava, Slovak Republic. http://www.molinspiration.com/cgi-bin/properties. Accessed 28 May 2016
  31. Mosmann T (1983) Rapid colourimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  32. Orlikova B, Schnekenburger M, Zloh M, Golais F, Diederich M, Tasdemir D (2012) Natural chalcones as dual inhibitors of HDACs and NF-kB. Oncol Rep 28:797–805CrossRefPubMedPubMedCentralGoogle Scholar
  33. Palchaudhuri R, Hergenrother PJ (2007) DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. Curr Opin Biotechnol 18:497–503CrossRefPubMedGoogle Scholar
  34. Paul A, Bhattacharya S (2012) Chemistry and biology of DNA-binding small molecules. Curr Sci 102:213–231Google Scholar
  35. Pezzuto JM, Che CT, McPherson DD, Zhu JP, Topcu G, Erdelmeier CAJ, Cordell GA (1991) DNA as an affinity probe useful in the detection and isolation of biologically active natural products. J Nat Prod 54:1522–1530CrossRefPubMedGoogle Scholar
  36. Reddy MV, Akula B, Cosenza SC, Lee CM, Mallireddigari MR, Pallela VR, Subbaiah DR, Udofa A, Reddy EP (2012) Z)-1-Aryl-3-arylamino-2-propen-1-ones, highly active stimulators of tubulin polymerization: synthesis, structure _activity relationship (SAR), tubulin polymerization, and cell growth inhibition studies. J Med Chem 55:5174–5187CrossRefPubMedPubMedCentralGoogle Scholar
  37. Rida SM, Ashour FA, El-Hawash SAM, ElSemary MM, Badr MH (2007) Synthesis of some novel substituted purine derivatives as potential anticancer, anti-HIV-1 and antimicrobial agents. Arch Pharm Chem Life Sci 340:185–194CrossRefGoogle Scholar
  38. Rida SM, Ashour FA, El-Hawash SA, ElSemary MM, Badr MH, Shalaby MA (2005) Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents. Eur J Med Chem 40:949–959CrossRefPubMedGoogle Scholar
  39. Rostom SAF (2010) Polysubstituted pyrazoles, Part 6. Synthesis of some 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazol-3-carbonyl derivatives linked to nitrogenous heterocyclic ring systems as potential antitumor agents. Bioorg Med Chem 18:2767–2776CrossRefPubMedGoogle Scholar
  40. Rostom SAF, Badr MH, Abd El Razik HA, Ashour HMA, Abdel Wahab AE (2011) Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents. Arch Pharm Chem Life Sci 344:572–587CrossRefGoogle Scholar
  41. Rostom SAF, Faidallah HM, Radwan MF, Badr MH (2014) Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: synthesis and in vitro biological evaluation as antimicrobial and anticancer agents. Eur J Med Chem 76:170–181CrossRefPubMedGoogle Scholar
  42. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics. CA Cancer J Clin 66:7–30CrossRefPubMedGoogle Scholar
  43. Shi JB, Tang WJ, Li R, Liu XH (2015) Novel pyrazole-5-carboxamide and pyrazolopyrimidine derivatives: synthesis and anticancer activity. Eur J Med Chem 90:889–896CrossRefPubMedGoogle Scholar
  44. Srinivasa Reddy T, Ganga Reddy V, Kulhari H, Shukla R, Kamal A, Bansal V (2016) Synthesis of (Z)-1-(1,3-diphenyl-1H-pyrazol-4-yl)-3-(phenylamino)prop-2-en-1-one derivatives as potential anticancer and apoptosis inducing agents. Eur J Med Chem 117:157–166CrossRefPubMedGoogle Scholar
  45. Strocchi E, Fornari F, Minguzzi M, Gramantieri L, Milazzo M, Rebuttini V, Breviglieri S, Camaggi CM, Locatelli E, Bolondi L, Comes-Franchini M (2012) Design, synthesis and biological evaluation of pyrazole derivatives as potential multi-kinase inhibitors in hepatocellular carcinoma. Eur J Med Chem 48:391–401CrossRefPubMedGoogle Scholar
  46. Susnik I, Vorkapic-Furac J, Durakovic S, Koprivanac S, Lasinger J (1992) Synthesis of some schiff bases of 3-aroyl-6-aryl-4-hydroxy-2H-pyran-2-ones. Monatsh Chem 123:817–822CrossRefGoogle Scholar
  47. Szliszka E, Czuba ZP, Mazur B, Paradysz A, Krol W (2010) Chalcones and dihydrochalcones augment TRAIL-mediated apoptosis in prostate cancer cells. Molecules 15:5336–5353CrossRefPubMedGoogle Scholar
  48. Thurston DE (1999) Nucleic acid targeting: therapeutic strategies for the 21st century. Br J Cancer 80(Suppl. 1):65–85PubMedGoogle Scholar
  49. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623CrossRefPubMedGoogle Scholar
  50. Wang M, Yu Y, Liang C, Lu A, Zhang G (2016) Recent advances in developing small molecules targeting nucleic acid. Int J Mol Sci 17:779–802CrossRefPubMedCentralGoogle Scholar
  51. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844CrossRefPubMedGoogle Scholar
  52. World Health Organization. Media Centre, Cancer, http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed 23 April 2016
  53. Xu S, Li S, Tang Y, Zhang J, Wang S, Zhou C, Li X (2013) Design, synthesis, and biologic evaluation of some novel n-arylpyrazole derivatives as cytotoxic agents. Med Chem Res 22:5610–5616CrossRefGoogle Scholar
  54. Youssef AM, Malki A, Badr MH, Elbayaa RY, Sultan AS (2012) Synthesis and anticancer activity of novel benzimidazole and benzothiazole derivatives against HepG2 liver cancer cells. Med Chem 8:151–162CrossRefPubMedGoogle Scholar
  55. Zhao Y, Abraham MH, Lee J, Hersey A, Luscombe NC, Beck G, Sherborne B, Cooper I (2002) Rate-limited steps of human oral absorption and QSAR studies. Pharm Res 19:1446–1457CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical ChemistryFaculty of Pharmacy, Alexandria UniversityAlexandriaEgypt

Personalised recommendations