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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

New Pyridinium Salt Derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5- sulfonamide as Selective Inhibitors of Tumour-Related Human Carbonic Anhydrase Isoforms IX and XII

Author(s): Özlen Güzel-Akdemir, Kübra Demir-Yazıcı, Daniela Vullo, Claudiu T. Supuran and Atilla Akdemir*

Volume 22, Issue 14, 2022

Published on: 24 March, 2022

Page: [2637 - 2646] Pages: 10

DOI: 10.2174/1871520622666220207092123

Price: $65

Abstract

Background: The positively charged membrane impermeant sulfonamides were evaluated as a remarkable class of carbonic anhydrase inhibitors (CAIs) previously. Without affecting the human carbonic anhydrase (hCA), cytosolic isoforms hCA I and II, inhibition of two membrane-associated isoforms hCA IX and XII especially overexpressed in hypoxic tumour cells, makes the pyridinium salt derivatives potent promising therapeutic agents.

Objective: A novel series of tri, tetra, and cyclo-substituted pyridinium salt derivatives of the lead compound 2- (hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide has been prepared by using sixteen different pyrylium salts, for the search of selective inhibitors of transmembrane tumour-associated human carbonic anhydrase hCA IX and XII.

Methods: Molecular modeling studies were carried out to understand and rationalize the in vitro enzyme inhibition data.

Results: Six of the new compounds showed good inhibitory profiles with low nanomolar range (< 100 nM) against hCA IX/XII, and compound 5 showed excellent potency with Ki values lower than 10 nM. In addition, molecular modelling studies have presented the possible binding modes of the ligands.

Conclusion: Most of the compounds displayed potent inhibitory activity against the tumor-associated hCA IX and XII in the low nanomolar range and selectivity over the off-targeted isoforms hCA I and II. Due to their cationic structure and membrane-impermeant behavior, it is also expected to maximize the selectivity over cytosolic isoforms hCA I/II while inhibiting tumor overexpressed isoforms hCA XI/XII of new compounds in in vivo conditions.

Keywords: Carbonic anhydrase, tumour-associated isoform, hCA IX/XII, sulfonamide, pyridinium salt, anticancer agent, molecular modelling, molecular dynamics simulations.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
World Health Organization. Cancer Homepage. Available from: https://www.who.int/health-topics/cancer#tab=tab_1 Accessed February 28, 2021)
[3]
World Health Organization. Cancer Homepage. Available from: https://www.who.int/news-room/facts-in-pictures/detail/cancer (Accessed February 28, 2021).
[4]
World Health Organization. Cancer Homepage. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer (Accessed February 28, 2021)
[5]
Dawson, M.A.; Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell, 2012, 150(1), 12-27.
[http://dx.doi.org/10.1016/j.cell.2012.06.013] [PMID: 22770212]
[6]
Brahimi-Horn, M.C.; Chiche, J.; Pouysségur, J. Hypoxia and cancer. J. Mol. Med. (Berl.), 2007, 85(12), 1301-1307.
[http://dx.doi.org/10.1007/s00109-007-0281-3] [PMID: 18026916]
[7]
Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis, 2018, 7(1), 10.
[http://dx.doi.org/10.1038/s41389-017-0011-9] [PMID: 29362402]
[8]
Trédan, O.; Galmarini, C.M.; Patel, K.; Tannock, I.F. Drug resistance and the solid tumor microenvironment. J. Natl. Cancer Inst., 2007, 99(19), 1441-1454.
[http://dx.doi.org/10.1093/jnci/djm135] [PMID: 17895480]
[9]
Dang, C.V.; Semenza, G.L. Oncogenic alterations of metabolism. Trends Biochem. Sci., 1999, 24(2), 68-72.
[http://dx.doi.org/10.1016/S0968-0004(98)01344-9] [PMID: 10098401]
[10]
Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009, 324(5930), 1029-1033.
[http://dx.doi.org/10.1126/science.1160809] [PMID: 19460998]
[11]
Wilson, W.R.; Hay, M.P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer, 2011, 11(6), 393-410.
[http://dx.doi.org/10.1038/nrc3064] [PMID: 21606941]
[12]
Patiar, S.; Harris, A.L. Role of hypoxia-inducible factor-1α as a cancer therapy target. Endocr. Relat. Cancer, 2006, 13(Suppl. 1), S61-S75.
[http://dx.doi.org/10.1677/erc.1.01290] [PMID: 17259560]
[13]
Supuran, C.T. Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opin. Investig. Drugs, 2018, 27(12), 963-970.
[http://dx.doi.org/10.1080/13543784.2018.1548608] [PMID: 30426805]
[14]
Supuran, C.T. Carbonic anhydrase inhibition and the management of hypoxic tumors. Metabolites, 2017, 7(3), 48.
[PMID: 28926956]
[15]
Angeli, A.; Carta, F.; Nocentini, A.; Winum, J.Y.; Zalubovskis, R.; Akdemir, A.; Onnis, V.; Eldehna, W.M.; Capasso, C.; Simone, G.; Monti, S.M.; Carradori, S.; Donald, W.A.; Dedhar, S.; Supuran, C.T. Carbonic anhydrase inhibitors targeting metabolism and tumor micro-environment. Metabolites, 2020, 10(10), 412.
[http://dx.doi.org/10.3390/metabo10100412] [PMID: 33066524]
[16]
Graham, K.; Unger, E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int. J. Nanomedicine, 2018, 13, 6049-6058.
[http://dx.doi.org/10.2147/IJN.S140462] [PMID: 30323592]
[17]
Nocentini, A.; Supuran, C.T. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008-2018). Expert Opin. Ther. Pat., 2018, 28(10), 729-740.
[http://dx.doi.org/10.1080/13543776.2018.1508453] [PMID: 30074415]
[18]
Neri, D.; Supuran, C.T. Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discov., 2011, 10(10), 767-777.
[http://dx.doi.org/10.1038/nrd3554] [PMID: 21921921]
[19]
Pastorekova, S.; Gillies, R.J. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev., 2019, 38(1-2), 65-77.
[http://dx.doi.org/10.1007/s10555-019-09799-0] [PMID: 31076951]
[20]
Casini, A.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, L.T. Sulfonamides and sulfonylated derivatives as anticancer agents. Curr. Cancer Drug Targets, 2002, 2(1), 55-75.
[http://dx.doi.org/10.2174/1568009023334060] [PMID: 12188921]
[21]
Carta, F.; Supuran, C.T.; Scozzafava, A. Sulfonamides and their isosters as carbonic anhydrase inhibitors. Future Med. Chem., 2014, 6(10), 1149-1165.
[http://dx.doi.org/10.4155/fmc.14.68] [PMID: 25078135]
[22]
Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist? J. Enzyme Inhib. Med. Chem., 2016, 31(3), 345-360.
[http://dx.doi.org/10.3109/14756366.2015.1122001] [PMID: 26619898]
[23]
Supuran, C.T.; De Simone, G. Carbonic Anhydrases as Biocatalysts, 1st ed; Elsevier: Amsterdam, The Netherlands, 2016.
[24]
Supuran, C.T.; Scozzafava, A.; Ilies, M.A.; Iorga, B.; Cristea, T.; Briganti, F.; Chiraleu, F.; Banciu, M.D. Carbonic anhydrase inhibitors - part 53. synthesis of substituted-pyridinium derivatives of aromatic sulfonamides: the first non-polymeric membrane-impermeable inhibi-tors with selectivity for isozyme IV. Eur. J. Med. Chem., 1998, 33(7-8), 577-594.
[http://dx.doi.org/10.1016/S0223-5234(98)80017-2]
[25]
Pastorekova, S.; Casini, A.; Scozzafava, A.; Vullo, D.; Pastorek, J.; Supuran, C.T. Carbonic anhydrase inhibitors: the first selective, mem-brane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg. Med. Chem. Lett., 2004, 14(4), 869-873.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.029] [PMID: 15012984]
[26]
Supuran, C.T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7(2), 168-181.
[http://dx.doi.org/10.1038/nrd2467] [PMID: 18167490]
[27]
Casey, J.R.; Morgan, P.E.; Vullo, D.; Scozzafava, A.; Mastrolorenzo, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX. J. Med. Chem., 2004, 47(9), 2337-2347.
[http://dx.doi.org/10.1021/jm031079w] [PMID: 15084132]
[28]
Akocak, S.; Güzel-Akdemir, Ö.; Kishore Kumar Sanku, R.; Russom, S.S.; Iorga, B.I.; Supuran, C.T.; Ilies, M.A. Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII. Bioorg. Chem., 2020, 103104204.
[http://dx.doi.org/10.1016/j.bioorg.2020.104204] [PMID: 32891000]
[29]
Ergenç, N.; Salman, A.; Gürsoy, A. Bankaolu, G. Synthesis and antifungal evaluation of some 3-phenyl-2,5-disubstituted indoles de-rived from new ethyl-2-benzyl-2-[N-(aryl)hydrazono] ethanoates. Pharmazie, 1990, 45(5), 346-347.
[http://dx.doi.org/10.1002/chin.199046177] [PMID: 2395897]
[30]
Güzel, O.; Temperini, C.; Innocenti, A.; Scozzafava, A.; Salman, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Interaction of 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide with 12 mammalian isoforms: kinetic and X-ray crystallographic studies. Bioorg. Med. Chem. Lett., 2008, 18(1), 152-158.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.110] [PMID: 18024029]
[31]
Güzel, O.; Innocenti, A.; Scozzafava, A.; Salman, A.; Parkkila, S.; Hilvo, M.; Supuran, C.T. Carbonic anhydrase inhibitors: synthesis and inhibition studies against mammalian isoforms I-XV with a series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides. Bioorg. Med. Chem., 2008, 16(20), 9113-9120.
[http://dx.doi.org/10.1016/j.bmc.2008.09.032] [PMID: 18819811]
[32]
Güzel, O.; Maresca, A.; Scozzafava, A.; Salman, A.; Balaban, A.T.; Supuran, C.T. Carbonic anhydrase inhibitors. Synthesis of 2,4,6-trimethylpyridinium derivatives of 2-(hydrazinocarbonyl)-3-aryl-1H-indole-5-sulfonamides acting as potent inhibitors of the tumor-associated isoform IX and XII. Bioorg. Med. Chem. Lett., 2009, 19(11), 2931-2934.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.068] [PMID: 19410461]
[33]
Khalifah, R.G. The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J. Biol. Chem., 1971, 246(8), 2561-2573.
[http://dx.doi.org/10.1016/S0021-9258(18)62326-9] [PMID: 4994926]
[34]
Vullo, D.; Innocenti, A.; Nishimori, I.; Pastorek, J.; Scozzafava, A.; Pastoreková, S.; Supuran, C.T. Carbonic anhydrase inhibitors. Inhibi-tion of the transmembrane isozyme XII with sulfonamides-a new target for the design of antitumor and antiglaucoma drugs? Bioorg. Med. Chem. Lett., 2005, 15(4), 963-969.
[http://dx.doi.org/10.1016/j.bmcl.2004.12.053] [PMID: 15686894]
[35]
Labute, P. Protonate3D: assignment of ionization states and hydrogen coordinates to macromolecular structures. Proteins, 2009, 75(1), 187-205.
[http://dx.doi.org/10.1002/prot.22234] [PMID: 18814299]
[36]
Labute, P. The generalized Born/volume integral implicit solvent model: estimation of the free energy of hydration using London disper-sion instead of atomic surface area. J. Comput. Chem., 2008, 29(10), 1693-1698.
[http://dx.doi.org/10.1002/jcc.20933] [PMID: 18307169]
[37]
Phillips, J.C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R.D.; Kalé, L.; Schulten, K. Scalable molecu-lar dynamics with NAMD. J. Comput. Chem., 2005, 26(16), 1781-1802.
[http://dx.doi.org/10.1002/jcc.20289] [PMID: 16222654]
[38]
Baeyer, A.; Piccard, J. Untersuchungen über das dimethylpyron. Justus Liebigs Ann. Chem., 1911, 384(2), 208-224.
[http://dx.doi.org/10.1002/jlac.19113840205]
[39]
Balaban, A.T.; Dinculescu, A.; Dorofeenko, G.N.; Fischer, G.W.; Koblik, A.V.; Mezheritskii, V.V.; Schroth, W. Pyrylium Salts: Syntheses, Reactions and Physical Properties; Academic Press: New York, 1982.
[40]
Balaban, A.T.; Toma, C. Reactions of pyrylium salts with nucleophiles—IV: isolation of an intermediate in the conversion of 2, 4, 6-triphenylpyrylium perchlorate into 2, 4, 6-triphenylpyridine by ammonia. Tetrahedron, 1966, 22, 1-8.
[41]
Katritzky, A.R.; Lloyd, J.M.; Patel, R.C. The preparation of pyridiniums from pyryliums. J. Chem. Soc., Perkin Trans. 1, 1982, 117-123.
[http://dx.doi.org/10.1039/p19820000117]
[42]
Akdemir, A.; Güzel-Akdemir, O.; Scozzafava, A.; Capasso, C.; Supuran, C.T. Inhibition of tumor-associated human carbonic anhydrase isozymes IX and XII by a new class of substituted-phenylacetamido aromatic sulfonamides. Bioorg. Med. Chem., 2013, 21(17), 5228-5232.
[http://dx.doi.org/10.1016/j.bmc.2013.06.029] [PMID: 23842519]
[43]
Kudryavtseva, V.; Boi, S.; Read, J.; Guillemet, R.; Zhang, J.; Udalov, A.; Shesterikov, E.; Tverdokhlebov, S.; Pastorino, L.; Gould, D.J.; Sukhorukov, G.B. Biodegradable defined shaped printed polymer microcapsules for drug delivery. ACS Appl. Mater. Interfaces, 2021, 13(2), 2371-2381.
[http://dx.doi.org/10.1021/acsami.0c21607] [PMID: 33404209]
[44]
Rutkowski, S.; Si, T.; Gai, M.; Sun, M.; Frueh, J.; He, Q. Magnetically-guided hydrogel capsule motors produced via ultrasound assisted hydrodynamic electrospray ionization jetting. J. Colloid Interface Sci., 2019, 541, 407-417.
[http://dx.doi.org/10.1016/j.jcis.2019.01.103] [PMID: 30710823]

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