In vitro inhibition of purified human carbonic anhydrase I and II by novel fluorene derivatives
Keywords:9-benzylidene-9H-fluorene, urea, thiourea, carbonic anhydrase, inhibition
In this study, 9-benzylidene-9H-fluorene-substituted urea (5a–p) and thiourea derivatives (5q–v) were synthesized and their inhibitory effects on the activity of human carbonic anhydrase (hCA) I and II were evaluated. hCA I and II were purified from human erythrocytes using a Sepharose 4B-L-tyrosine-sulphanilamide affinity column. All the synthesized compounds inhibited the activity of the hCA I and II isoenzymes. Among the synthesized compounds, 5f was found to be the most active (IC50 = 21.4 μM) for inhibition of hCA I and 5s was the most active (IC50 = 25.3 μM) for inhibition of hCA II.
M. S. Novikov, A. F. Khlebnikov, M. A. Egarmin, M. V. Shevchenko, V. A. Khlebnikov, R. R. Kostikov, D. Vidovic, Regioselectivity of the 1,3-Dipolar Cycload-dition of Fluorinated Fluoren-9-iminium Ylides to Het-eroelement-Containing Dipolarophiles: Experi¬men¬tal and Quantum-Chemical Study, Russian J. Org. Chem., 42, 1800–1812 (2006).
V. Lukes, D. Vegh, P. Hrdlovic, M. Stefko, K. Matuszna, V. Laurinc, Synthesis, theoretical characterisation and spectra of thiophene-fluorene π-conjugated derivatives, Synthetic Metals, 148, 179–186 (2005).
S. L. Tao, Z. K. Peng, X. H. Zhang, P. F. Wang, C. S. Lee, S. T. Lee, Highly Efficient Non-Doped Blue Or-ganic Light-Emitting Diodes Based on Fluorene Derivatives with High Thermal Stability, Advanced Functional Mat., 15, 1716–1721 (2005).
G. Hsu, J. R. Kiefer, D. Burnouf, O. J. Becherel, R. P. P. Fuchs, L. S. Beese, Observing Translesion Synthesis of an Aromatic Amine DNA Adduct by a High-fidelity DNA Polymerase, J. Biol. Chem., 279, 50280–50285 (2004).
S. Schulman, Fluorene Derivatives for Cancer Research, J. Org. Chem., 14, 382–387 (1949).
L. A. Pinck, On the Carcinogenesis of 2-Substituted Fluorenes, Comments and Communications, 109, 209 (1949).
PATENT: S. Ahmed, P. C. Gambacorti, P. G. Goekjian, D. Gueyrard, R. H. Gunby, F. Popowycz, L. Scapozza, C. Schneider, A. Zambon, US20110112110 A1; (2011).
P. Marinova, M. Marinov, Y. Feodorova, M. Kazakova, D. Georgiev, E. Trendafilova, P. Penchev, V. Sarafian, N. Stoyanov, Synthesis, antimicrobial and in vitro antiproliferative activity of 4'-bromo-(9'-fluorene)-spiro-5-(2,4-dithiohydantoin) against tumor cells, Scientific Works: University of Ruse “Angel Kanchev” 52, 33–37 (2013).
B. Beije, L. Möller, 2-nitrofluorene and related com-pounds: prevalence and biological effects, Mutation Research/Reviews in Genetic Toxicology, 196, 177–209 (1988).
C. Jing, L. Yang, F. Junxiang, 9-Benzylidene-9H-fluorene Derivatives Linked to Monoaza-15-crown-5: Synthesis and Metal Ion Sensing, Chin. J. Chem., 30, 1571–1574 (2012).
M. Houimel, J-P. Mach, I. Corthésy-Theulaz, B. Corthésy, I. Fisch, New inhibitors of Helicobacter pylori urease holoenzyme selected from phage-displayed peptide libraries, Eur. J. Biochem., 262, 774–780 (1999).
I. J. M. Rosenstein, J. M. T. Hamilton-Miller, D. M. Musher, Inhibitors of urease as chemotherapeutic agents, Crit. Rev. Microbiol., 11, 1–12 (1984).
H. Dulude, R. Salvador, G. Gallant, Synthesis and anti-HIV activity of new urea and nitrosourea derivatives of diamino acids, Bioorg. Med. Chem, 3, 151–160 (1995).
N. Gencer, D. Demir, F. Sonmez, M. Kucukislamoglu, New saccharin derivatives as tyrosinase inhibitors, Bioorg. Med. Chem., 20, 2811–2821 (2012).
A. R. Nixha, M. Arslan, Y. Atalay, N. Gencer, A. Ergun, O. Arslan, Synthesis and theoretical calculations of carbazole substituted chalcone urea derivatives and studies their polyphenol oxidase enzyme activity, J. Enzyme Inhib. Med. Chem., 28, 808–815 (2013).
G. Madhava, K. Venkata Subbaiah, R. Sreenivasulu, C. Naga Raju, Synthesis of novel urea and thiourea derivatives of diphenylphosphoramidate and their antimicrobial activity Der Pharmacia Lettre, 4, 1194–1201 (2012).
M. Avalos, R. Babiano, P. Cintas, M. M. Chavero, F. J. Higes, J. L. Jimenez, J. C. Palacıos, G. Sılvero, Reac-tions of 2-amino-2-thiazolines with isocyanates and isothiocyanates. Chemical and computational studies on the regioselectivity, adduct rearrangement, and mechanistic pathways, J. Org. Chem., 65, 8882–8892 (2000).
M. D’hooghe, N. De Kimpe, Synthetic approaches towards 2-iminothiazolidines: an overview, Tetrahe-dron, 62, 513–535 (2006).
F. Pacchiano, F. Carta, P. C. McDonald, Y. Lou, D. Vullo, A. Scozzafava, S. Dedhar, C. T. Supuran, Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis, J. Med. Chem., 54, 1896–1902 (2011).
C. T. Supuran, Carbonic anhydrases: novel therapeutic applications for inhibitors and activators, Nat. Rev. Drug Disc., 7, 168-181 (2008).
A. Thiry, J. M. Dogné, B. Masereel, C. T. Supuran, Targeting tumor associated carbonic anhydrase IX in cancertherapy, Trends Pharmacol. Sci., 27, 566–573 (2006).
J. M. McKiernan, R. Buttyan, N. H. Bander, M. D. Stifelman, A. E. Katz, M. W. Chen, C. A. Olsson, I. S. Sawczuk, Expression of the tumor-associated gene MN: A potential biomarker for human renal cell carcinoma, Cancer Res., 57, 2362–2365 (1997).
A. Scozzafava, A. Mastrolorenzo, C.T. Supuran, Car-bonic anhydrase inhibitors and activators and their use in therapy, Expert Opin. Ther. Pat., 16, 1627–1664 (2006).
C. T. Supuran, A. Scozzafava, A. Casini, Carbonic anhy¬drase inhibitors, Med. Res. Rev., 23, 146–189 (2003).
K. S. Smith, J. G. Ferry, Prokaryotic carbonic anhy-drases, FEMS Microbiol. Rev., 24, 335–366 (2000).
T. Stams, D. W. Christianson, The Carbonic Anhy-drases: New Horizons, Birkhauser Verlag, Boston, 2000, pp. 159–174.
S. Pastorekova, S. Parkkila, J. Pastorek, C. T. Supuran, Carbonic anhydrases: Current state of the art, therapeutic applications and future prospects, J. Enzyme. Inhib. Med. Chem., 19, 199–229 (2004).
I. Nishimori, T. Minakuchi, S. Onishi, D. Vullo, A. Cecchi, A. Scozzafava, C. T. Supuran, Carbonic anhy-drase inhibitors: Cloning, characterization, and inhibi-tion studies of the cytosolic isozyme III with sulphonamides, Bioorg. Med. Chem., 15, 7229–7236 (2007).
I. Nishimori, D. Vullo, A. Innocenti, A. Scozzafava, A. Mastrolorenzo, C. T. Supuran, Carbonic anhydrase inhibitors. The mitochondrial isozyme VB as a new target for sulfonamide and sulfamate inhibitors, J. Med. Chem., 48, 7860–7866 (2005).
D. Vullo, J. Voipio, A. Innocenti, C. Rivera, H. Ranki, A. Scozzafava, K. Kaila, C. T. Supuran, Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulphonamides, Bioorg. Med. Chem. Lett., 15, 971–976 (2005).
C. T. Supuran, A. Scozzafava, J. Conway, Carbonic Anhydrase: Its Inhibitors and Activators, CRC Press, Boca Raton, 2004, pp. 25–43.
D. Vullo, M. Franchi, E. Gallori, J. Pastorek, A. Scoz-zafava, S. Pastorekova, C. T. Supuran, Carbonic anhy-drase inhibitors: Inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulphon-amides, Bioorg. Med. Chem. Lett. 13, 1005–1009 (2003).
D. Vullo, A. Innocenti, I. Nishimori, J. Pastorek, A. Scozzafava, S. Pastoreková, C. T. Supuran, Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides-a new target for the design of antitumor and antiglaucoma drugs, Bioorg. Med. Chem., Lett. 15, 963–969 (2005).
J. Lehtonen, B. Shen, M. Vihinen, A. Casini, A. Scoz-zafava, C. T. Supuran, A. K. Parkkila, J. Saarnio, A. J. Kivela, A. Waheed, W. S. Sly, S. Parkkila, Characterization of CA XIII, a novel member of the carbonic anhydrase isozyme family, J. Biol. Chem., 279, 2719–2727 (2004).
I. Nishimori, D. Vullo, A. Innocenti, A. Scozzafava, A. Mastrolorenzo, C.T. Supuran, Carbonic anhydrase inhibitors: Inhibition of the transmembrane isozyme XIV with sulphonamides, Bioorg. Med. Chem. Lett., 15, 3828–3833 (2005).
H. Demirhan, M. Arslan, M. Zengin, M. Kucukislamo-glu, A Comparative Study in Oxidative Free Radical Reactions between 9-Benzylidene-9H-fluorene Derivatives and β-Dicarbonyl Compounds in the Presence of Mn(OAc)3 and CAN, Lett. In Org. Chem., 8, 488–494 (2011).
R. Annunziata, V. Molteni, L. Raimondi, Synthesis and structural assignment of 2,4'-disubstituted benzylidenefluorenes and 4'-substituted benzylidene-1-azafluorenes, Magn. Reson. Chem., 36, 520–528 (1998).
O. Arslan, B. Nalbantoglu, N. Demir, H. Ozdemir, O. I. Kufrevioglu, A new method for the purification of carbonic anhyrase isozymes by affinity chromatography, Turk. J. Med. Sci., 26, 163–166 (1996).
T. H. Maren, A simplified micromethod for the determination of carbonic anhydrase and its inhibitors, J. Pharm. Exp. Ther., 130, 2629–2634 (1960).
F. Pacchiano, M. Aggarwal, B. S. Avvaru, A. H. Rob-bins, A. Scozzafava, R. McKenna, C. T. Supuran, Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency, Chem. Commun., 46, 8371–8373 (2010).
K. Erol, N. Gencer, M. Arslan, O. Arslan, Purification, characterization, and investigation of in vitro inhibition by metals of paraoxonase from different sheep breeds, Artif. Cells Nanomed. Biotechnol., 41, 125–130 (2013).
N. Gencer, A. Ergun, D. Demir, In vitro effects of some anabolic compounds on erythrocyte carbonic anhydrase I and II, J. Enzyme Inhib. Med. Chem., 27, 208–210 (2012).
N. Berber, M. Arslan, E. Yavuz, C. Bilen, N. Gencer, Synthesis and Evaluation of New Phthalazine Urea and Thiourea Derivatives as Carbonic Anhydrase Inhibitors, J. Chem., 2013, 1–8 (2013).
D. Demir, N. Gencer, A. Er, Purification and characterization of prophenoloxidase from Galleria mellonella L. Artif. Cells Nanomed. Biotechnol., 40, 391–395 (2012).
B. Gokce, N. Gencer, O. Arslan, S. A. Turkoglu, M. Alper, F. Kockar, Evaluation of in vitro effects of some analgesic drugs on erythrocyte and recombinant carbonic anhydrase I and II, J. Enzyme Inhib. Med. Chem., 7, 37–42 (2012).
How to Cite
The authors agree to the following licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material
- for any purpose, even commercially.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- NonCommercial — You may not use the material for commercial purposes.