Aryl azide-sulfonamide hybrids induce cellular apoptosis: synthesis and preliminary screening of their cytotoxicity in human HCT116 and A549 cancer cell lines

  • Ahmed El-Kardocy
  • Muhamad Mustafa
  • Esam R. Ahmed
  • Samy Mohamady
  • Yaser A. MostafaEmail author
Original Research


Simple, small, drug-like molecules bearing aryl azide and aryl sulfonamide moieties were designed and synthesized. The cytotoxic activity of these compounds was measured on colon cancer HCT116, lung cancer A549, and normal fibroblast cells F180 cell lines. All the synthesized compounds showed a significant cytotoxic activity below 100 µM in both HCT116 and A549 cells. Compounds 10e and 10f exhibited the most potent activity with IC50 values of 2.20 and 6.27 µM on A549 and HCT116 cells, respectively. Also, compounds 10e and 10f showed significant tumor selectivity on HCT116 and A549 cell lines when compared with the reference cytotoxic agent staurosporine. This indicated the promising safety of these compounds on normal cells. In addition, flow cytometry studies showed that HCT116 cell lines treated with the most active compound 10f were arrested in the G2/M phase of the cell cycle. 10f boosted both early and late apoptosis at HCT116 cells. A hypothetical pharmacophore model was built using 14 reported potent carbonic anhydrase I inhibitors. The pharmacophoric study revealed that the tested sulfonamide derivatives 10e and 10f showed significant fitting on the pharmacophore query with reasonable RMSD values. Molecular docking study showed a chelation reaction with the key Zn atom, in addition to different hydrogen bonding, and van der Waals interactions with several important amino acids inside the CA Ι active site.


Sulfonamides Cytotoxicity Carbonic anhydrase Molecular docking Pharmacophoric study 



The authors extend their appreciation to faculty of Pharmacy, the British University in Egypt and the Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University for their support to synthesis these azide-sulfonamides and perform the preliminary cytotoxic studies. Special thanks to Assoc. Prof. Ahmed S. Aboraia for helping in performing the pharmacophoric study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alaoui S, Dufies M, Driowya M, Demange L, Bougrin K, Robert G et al. (2017) Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides. Bioorg Med Chem Lett 27(9):1989–1992CrossRefGoogle Scholar
  2. Arslan O, Çakir Ü, Uğraş H (2002) Synthesis of new sulfonamide inhibitors of carbonic anhydrase. Biochemistry 67(9):1055–1057Google Scholar
  3. Bagheri F, Safarian S, Eslaminejad MB, Sheibani N (2014) Stable overexpression of DNA fragmentation factor in T-47D cells: sensitization of breast cancer cells to apoptosis in response to acetazolamide and sulfabenzamide. Mol Biol Rep 41(11):7387–7394. CrossRefGoogle Scholar
  4. Barathova M, Takacova M, Holotnakova T, Gibadulinova A, Ohradanova A, Zatovicova M et al. (2008) Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype. Br J Cancer 98(1):129CrossRefGoogle Scholar
  5. Bekku S, Mochizuki H, Yamamoto T, Ueno H, Takayama E, Tadakuma T (2000) Expression of carbonic anhydrase I or II and correlation to clinical aspects of colorectal cancer. Hepato-Gastroenterology 47(34):998–1001Google Scholar
  6. Boztas M, Cetinkaya Y, Topal M, Gulcin I, Menzek A, Sahin E et al. (2014) Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties. J Med Chem 58(2):640–650CrossRefGoogle Scholar
  7. Bruno E, Buemi MR, De Luca L, Ferro S, Monforte AM, Supuran CT et al. (2016) In vivo evaluation of selective carbonic anhydrase inhibitors as potential anticonvulsant agents. ChemMedChem 11(16):1812–1818CrossRefGoogle Scholar
  8. Budak Y, Kocyigit UM, Gürdere MB, Özcan K, Taslimi P, Gülçin İ et al. (2017) Synthesis and investigation of antibacterial activities and carbonic anhydrase and acetyl cholinesterase inhibition profiles of novel 4,5-dihydropyrazol and pyrazolyl-thiazole derivatives containing methanoisoindol-1,3-dion unit. Synth Commun 47(24):2313–2323CrossRefGoogle Scholar
  9. Bulut N, Kocyigit U, Gecibesler I, Dastan T, Karci H, Taslimi P et al. (2017) Synthesis of some novel pyridine compounds containing bis-124-triazole/thiosemicarbazide moiety and investigation of their antioxidant properties carbonic anhydrase and acetylcholinesterase enzymes inhibition profiles. J Biochem Mol Toxicol 32(1):1–10 (e22006)Google Scholar
  10. Carradori S, Mollica A, De Monte C, Granese A, Supuran C (2015) Nitric oxide donors and selective carbonic anhydrase inhibitors: a dual pharmacological approach for the treatment of glaucoma, cancer and osteoporosis. Molecules 20(4):5667–5679CrossRefGoogle Scholar
  11. Ceylan M, Kocyigit UM, Usta NC, Gürbüzlü B, Temel Y, Alwasel SH et al. (2017) Synthesis, carbonic anhydrase I and II isoenzymes inhibition properties, and antibacterial activities of novel tetralone‐based 1,4‐benzothiazepine derivatives. J Biochem Mol Toxicol 31(4):e21872CrossRefGoogle Scholar
  12. da Cruz EH, Silvers MA, Jardim GA, Resende JM, Cavalcanti BC, Bomfim IS et al. (2016) Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights. Eur J Med Chem 122:1–16CrossRefGoogle Scholar
  13. El-Awady RA, Semreen MH, Saber-Ayad MM, Cyprian F, Menon V, Al-Tel TH (2016) Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells. DNA Repair 37:1–11CrossRefGoogle Scholar
  14. El-Din MMG, El-Gamal MI, Abdel-Maksoud MS, Yoo KH, Oh C-H (2015) Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety. Eur J Med Chem 90:45–52CrossRefGoogle Scholar
  15. Eldehna WM, Abo-Ashour MF, Nocentini A, Gratteri P, Eissa IH, Fares M et al. (2017) Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene) thiazolidin-2-ylidene) amino) benzenesulfonamides: synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies. Eur J Med Chem 139:250–262CrossRefGoogle Scholar
  16. Fu D-J, Fu L, Liu Y-C, Wang J-W, Wang Y-Q, Han B-K et al. (2017) Structure-activity relationship studies of β-lactam-azide analogues as orally active antitumor agents targeting the tubulin colchicine site. Sci Rep 7(1):12788CrossRefGoogle Scholar
  17. Gokcen T, Gulcin I, Ozturk T, Goren AC (2016) A class of sulfonamides as carbonic anhydrase I and II inhibitors. J Enzym Inhib Med Chem 31(sup2):180–188CrossRefGoogle Scholar
  18. Gondi G, Mysliwietz J, Hulikova A, Jen JP, Swietach P, Kremmer E et al. (2013) Antitumor efficacy of a monoclonal antibody that inhibits the activity of cancer-associated carbonic anhydrase XII. Cancer Res 73(21):6494–6503CrossRefGoogle Scholar
  19. Gul HI, Mete E, Taslimi P, Gulcin I, Supuran CT (2017) Synthesis, carbonic anhydrase I and II inhibition studies of the 1,3,5-trisubstituted-pyrazolines. J Enzym Inhib Med Chem 32(1):189–192CrossRefGoogle Scholar
  20. Gul HI, Tugrak M, Sakagami H, Taslimi P, Gulcin I, Supuran CT (2016) Synthesis and bioactivity studies on new 4-(3-(4-Substitutedphenyl)-3a,4-dihydro-3 H-indeno [1,2-c] pyrazol-2-yl) benzenesulfonamides. J Enzym Inhib Med Chem 31(6):1619–1624CrossRefGoogle Scholar
  21. Gulçin İ, Abbasova M, Taslimi P, Huyut Z, Safarova L, Sujayev A et al. (2017) Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors. J Enzym Inhibi Med Chem 32(1):1174–1182CrossRefGoogle Scholar
  22. Gulcin I, Beydemir S (2013) Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. Mini Rev Med Chem 13(3):408–430Google Scholar
  23. Hoeijmakers JH (2009) DNA damage, aging, and cancer. New Engl J Med 361(15):1475–1485CrossRefGoogle Scholar
  24. Hu W, Kavanagh JJ (2003) Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 4(12):721–729CrossRefGoogle Scholar
  25. Huang Q, Chen R, Lin X, Xiang Z (2017) Efficacy of carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa: a meta-analysis. PLoS ONE 12(10):e0186180CrossRefGoogle Scholar
  26. Jain AK, Veerasamy R, Vaidya A, Mourya V, Agrawal RK (2010) QSAR analysis of some novel sulfonamides incorporating 1,3,5-triazine derivatives as carbonic anhydrase inhibitors. Med Chem Res 19(9):1191–1202. CrossRefGoogle Scholar
  27. Kocyigit UM, Aslan ON, Gulcin I, Temel Y, Ceylan M (2016) Synthesis and carbonic anhydrase inhibition of novel 2‐(4‐(Aryl) thiazole‐2‐yl)‐3a,4,7,7a‐tetrahydro‐1H‐4,7‐methanoisoindole‐1,3 (2H)‐dione derivatives. Arch Pharm 349(12):955–963CrossRefGoogle Scholar
  28. Kocyigit UM, Budak Y, Eligüzel F, Taslimi P, Kılıç D, Gulçin İ et al. (2017) Synthesis and carbonic anhydrase inhibition of tetrabromo chalcone derivatives. Arch Pharm 350(12):1700198CrossRefGoogle Scholar
  29. Kucukoglu K, Oral F, Aydin T, Yamali C, Algul O, Sakagami H et al. (2016) Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines. J Enzym Inhib Med Chem 31(sup4):20–24CrossRefGoogle Scholar
  30. Legigan T, Clarhaut J, Renoux B, Tranoy-Opalinski I, Monvoisin A, Berjeaud J-M et al. (2012) Synthesis and antitumor efficacy of a β-glucuronidase-responsive albumin-binding prodrug of doxorubicin. J Med Chem 55(9):4516–4520CrossRefGoogle Scholar
  31. Lipeeva AV, Pokrovsky MA, Baev DS, Shakirov MM, Bagryanskaya IY, Tolstikova TG et al. (2015) Synthesis of 1H-1,2,3-triazole linked aryl (arylamidomethyl)–dihydrofurocoumarin hybrids and analysis of their cytotoxicity. Eur J Med Chem 100:119–128CrossRefGoogle Scholar
  32. Mete E, Comez B, Inci Gul H, Gulcin I, Supuran CT (2016) Synthesis and carbonic anhydrase inhibitory activities of new thienyl-substituted pyrazoline benzenesulfonamides. J Enzym Inhib Med Chem 31(sup2):1–5CrossRefGoogle Scholar
  33. Mirian M, Zarghi A, Sadeghi S, Tabaraki P, Tavallaee M, Dadrass O et al. (2011) Synthesis and cytotoxic evaluation of some novel sulfonamidederivativesagainst a few human cancer cells. Iran J Pharm Res 10(4):741Google Scholar
  34. Nicolaus N, Zapke J, Riesterer P, Neudörfl JM, Prokop A, Oschkinat H et al. (2010) Azides derived from colchicine and their use in library synthesis: a practical entry to new bioactive derivatives of an old natural drug. ChemMedChem 5(5):661–665CrossRefGoogle Scholar
  35. Pinney KG, Mejia MP, Villalobos VM, Rosenquist BE, Pettit GR, Verdier-Pinard P et al. (2000) Synthesis and biological evaluation of aryl azide derivatives of combretastatin A-4 as molecular probes for tubulin. Bioorg Med Chem 8(10):2417–2425CrossRefGoogle Scholar
  36. Prasanna Kumar BN, Mohana KN, Mallesha L, Veeresh B (2014) Synthesis and in vitro antiproliferative activity of 2,5-disubstituted-1,3,4-oxadiazoles containing trifluoromethyl benzenesulfonamide moiety. Med Chem Res 23(7):3363–3373. CrossRefGoogle Scholar
  37. Riafrecha LE, Rodríguez OM, Vullo D, Supuran CT, Colinas PA (2014) Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII. Bioorg Med Chem 22(19):5308–5314CrossRefGoogle Scholar
  38. Sabt A, Abdelhafez OM, El-Haggar RS, Madkour HM, Eldehna WM, El-Khrisy EE-DA et al. (2018) Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: synthesis, in vitro biological evaluation, and QSAR studies. J Enzym Inhib Med Chem 33(1):1095–1107CrossRefGoogle Scholar
  39. Salmon AJ, Williams ML, Wu QK, Morizzi J, Gregg D, Charman SA et al. (2012) Metallocene-based inhibitors of cancer-associated carbonic anhydrase enzymes IX and XII. J Med Chem 55(11):5506–5517CrossRefGoogle Scholar
  40. Spletstoser JT, Flaherty PT, Himes RH, Georg GI (2004) Synthesis and anti-tubulin activity of a 3′-(4-azidophenyl)-3′-dephenylpaclitaxel photoaffinity probe. J Med Chem 47(26):6459–6465CrossRefGoogle Scholar
  41. Tanabe K, Ishizaki J, Ando Y, Ito T, Nishimoto S-i (2012) Reductive activation of 5-fluorodeoxyuridine prodrug possessing azide methyl group by hypoxic X-irradiation. Bioorg Med Chem Lett 22(4):1682–1685CrossRefGoogle Scholar
  42. Taslimi P, Gulcin I, Ozgeris B, Goksu S, Tumer F, Alwasel SH et al. (2016) The human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibition effects of trimethoxyindane derivatives. J Enzym Inhib Med Chem 31(1):152–157CrossRefGoogle Scholar
  43. Thamilarasan V, Jayamani A, Sengottuvelan N (2015) Synthesis, molecular structure, biological properties and molecular docking studies on MnII, CoII and ZnII complexes containing bipyridine–azide ligands. Eur J Med Chem 89:266–278CrossRefGoogle Scholar
  44. Turkan F, Cetin A, Taslimi P, Karaman M, Gulçin İ (2019) Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorg Chem 86:420–427CrossRefGoogle Scholar
  45. Wang D-b, Lu X-k, Zhang X, Li Z-g, Li C-x (2016) Carbonic anhydrase 1 is a promising biomarker for early detection of non-small cell lung cancer. Tumor Biol 37(1):553–559CrossRefGoogle Scholar
  46. Yıldırım A, Atmaca U, Keskin A, Topal M, Celik M, Gülçin İ et al. (2015) N-Acylsulfonamides strongly inhibit human carbonic anhydrase isoenzymes I and II. Bioorg Med Chem 23(10):2598–2605CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ahmed El-Kardocy
    • 1
  • Muhamad Mustafa
    • 2
  • Esam R. Ahmed
    • 3
  • Samy Mohamady
    • 4
  • Yaser A. Mostafa
    • 5
    Email author
  1. 1.Student Research Center, Faculty of PharmacyAssiut UniversityAssiutEgypt
  2. 2.Pharmaceutical Chemistry Department, Faculty of PharmacyDeraya UniversityMinyaEgypt
  3. 3.VACSERACairoEgypt
  4. 4.Faculty of PharmacyThe British University in EgyptAl-SheroukEgypt
  5. 5.Pharmaceutical Organic Chemistry Department, Faculty of PharmacyAssiut UniversityAssiutEgypt

Personalised recommendations