Design and Synthesis of 2-substituted [1,2,4]Triazolo[1,5-a]pyrimidines Tethered with Umbelliferone as Selective Carbonic Anhydrase IX and XII Inhibitors


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Abstract

Objective: This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7’-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold.

Methods: The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells.

Results: In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with KI values ranging from 0.75 to 10.5 μM, while hCA I, II, IV isoforms were not significantly inhibited (KIs > 100 μM). Compound 3d emerged as the most potent and selective inhibitor, with KIs of 0.92 and 0.75 μM for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin.

Conclusion: In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices > 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

About the authors

Romeo Romagnoli

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara

Author for correspondence.
Email: info@benthamscience.net

Elena Romagnoli

Department of Life and Environmental Sciences, Polytechnic University of Marche

Email: info@benthamscience.net

Andrea Brancale

Department of Organic Chemistry, University of Chemistry and Technology

Email: info@benthamscience.net

Claudiu Supuran

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence

Email: info@benthamscience.net

Alessio Nocentini

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence

Email: info@benthamscience.net

Lorenzo Manfreda

Department of Woman’s and Child’s Health, Hemato-Oncology Lab, University of Padova

Email: info@benthamscience.net

Arianna Zanolli

Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza

Email: info@benthamscience.net

Roberta Bortolozzi

Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza

Author for correspondence.
Email: info@benthamscience.net

Giampietro Viola

Department of Woman’s and Child’s Health, Hemato-Oncology Lab, University of Padova

Email: info@benthamscience.net

References

  1. Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J., 2016, 473(14), 2023-2032. doi: 10.1042/BCJ20160115 PMID: 27407171
  2. Occhipinti, R.; Boron, W.F. Role of carbonic anhydrases and inhibitors in acid-base physiology: Insights from mathematical modeling. Int. J. Mol. Sci., 2019, 20(15), 3841-3871. doi: 10.3390/ijms20153841 PMID: 31390837
  3. Jensen, E.L.; Clement, R.; Kosta, A.; Maberly, S.C.; Gontero, B. A new widespread subclass of carbonic anhydrase in marine phytoplankton. ISME J., 2019, 13(8), 2094-2106. doi: 10.1038/s41396-019-0426-8 PMID: 31024153
  4. Aspatwar, A.; Haapanen, S.; Parkkila, S. An update on the metabolic roles of carbonic anhydrases in the model alga Chlamydomonas reinhardtii. Metabolites, 2018, 8(1), 22. doi: 10.3390/metabo8010022 PMID: 29534024
  5. Mboge, M.; Mahon, B.; McKenna, R.; Frost, S. Carbonic anhydrases: Role in pH control and cancer. Metabolites, 2018, 8(1), 19. doi: 10.3390/metabo8010019 PMID: 29495652
  6. Supuran, C. Carbonic anhydrases and metabolism. Metabolites, 2018, 8(2), 25. doi: 10.3390/metabo8020025 PMID: 29561812
  7. Supuran, C.T. Carbonic anhydrase versatility: From pH regulation to CO2 sensing and metabolism. Front. Mol. Biosci., 2023, 101326633 doi: 10.3389/fmolb.2023.1326633 PMID: 38028557
  8. Aspatwar, A.; Tolvanen, M.E.E.; Barker, H.; Syrjänen, L.; Valanne, S.; Purmonen, S.; Waheed, A.; Sly, W.S.; Parkkila, S. Carbonic anhydrases in metazoan model organisms: Molecules, mechanisms, and physiology. Physiol. Rev., 2022, 102(3), 1327-1383. doi: 10.1152/physrev.00018.2021 PMID: 35166161
  9. Akocak, S.; Supuran, C.T. Activation of α-, β-, γ- δ-, ζ- and η- class of carbonic anhydrases with amines and amino acids: A review. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1652-1659. doi: 10.1080/14756366.2019.1664501 PMID: 31530034
  10. Nocentini, A.; Donald, W.A.; Supuran, C.T. Human carbonic anhydrases: Tissue distribution, physiological role, and druggability.in: Carbonic Anhydrases; Elsevier: Amsterdam, Netherlands, 2019, pp. 151-186. doi: 10.1016/B978-0-12-816476-1.00008-3
  11. Hassan, I.M.; Shajee, B.; Waheed, A.; Ahmad, F.; Sly, W.S. Structure, function and applications of carbonic anhydrase isozymes. Bioorg. Med. Chem., 2013, 21(6), 1570-1582. doi: 10.1016/j.bmc.2012.04.044 PMID: 22607884
  12. Aggarwal, M.; Boone, C.D.; Kondeti, B.; McKenna, R. Structural annotation of human carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2013, 28(2), 267-277. doi: 10.3109/14756366.2012.737323 PMID: 23137351
  13. D’Ambrosio, K.; De Simone, G.; Supuran, C.T. Human carbonic anhydrases: Catalytic properties, structural features, and tissue distribution.Carbonic Anhydrases as Biocatalysts: From theory to Medical and Industrial Applications; Elsevier: Amsterdam, Netherlands, 2015, pp. 17-30. doi: 10.1016/B978-0-444-63258-6.00002-0
  14. Supuran, C.T. Emerging role of carbonic anhydrase inhibitors. Clin. Sci., 2021, 135(10), 1233-1249. doi: 10.1042/CS20210040 PMID: 34013961
  15. Zamanova, S.; Shabana, A.M.; Mondal, U.K.; Ilies, M.A. Carbonic anhydrases as disease markers. Expert Opin. Ther. Pat., 2019, 29(7), 509-533. doi: 10.1080/13543776.2019.1629419 PMID: 31172829
  16. Supuran, C.T. Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opin. Ther. Pat., 2018, 28(10), 709-712. doi: 10.1080/13543776.2018.1523897 PMID: 30217119
  17. Ji, M.J.; Hong, J.H. An overview of carbonic anhydrases and membrane channels of synoviocytes in inflamed joints. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1615-1622. doi: 10.1080/14756366.2019.1659791 PMID: 31480869
  18. Margheri, F.; Ceruso, M.; Carta, F.; Laurenzana, A.; Maggi, L.; Lazzeri, S.; Simonini, G.; Annunziato, F.; Del Rosso, M.; Supuran, C.T.; Cimaz, R. Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium J. Enzyme Inhib. Med. Chem., 2016, 31(sup4), 60-63. doi: 10.1080/14756366.2016.1217857 PMID: 27539792
  19. Buabeng, E.R.; Henary, M. Developments of small molecules as inhibitors for carbonic anhydrase isoforms. Bioorg. Med. Chem., 2021, 39116140 doi: 10.1016/j.bmc.2021.116140 PMID: 33905966
  20. Nocentini, A.; Supuran, C.T.; Capasso, C. An overview on the recently discovered iota-carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2021, 36(1), 1988-1995. doi: 10.1080/14756366.2021.1972995 PMID: 34482770
  21. Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C.T.; De Simone, G. Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms? Chem. Rev., 2012, 112(8), 4421-4468. doi: 10.1021/cr200176r PMID: 22607219
  22. T., Supuran C. Novel carbonic anhydrase inhibitors. Future Med. Chem., 2021, 13(22), 1935-1937. doi: 10.4155/fmc-2021-0222 PMID: 34498952
  23. Thiry, A.; Dogné, J.M.; Supuran, C.; Masereel, B. Carbonic anhydrase inhibitors as anticonvulsant agents. Curr. Top. Med. Chem., 2007, 7(9), 855-864. doi: 10.2174/156802607780636726 PMID: 17504130
  24. Mishra, C.B.; Tiwari, M.; Supuran, C.T. Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today? Med. Res. Rev., 2020, 40(6), 2485-2565. doi: 10.1002/med.21713 PMID: 32691504
  25. Lionetto, M.G. Carbonic anhydrase and biomarker research: New insights. Int. J. Mol. Sci., 2023, 24(11), 9687. doi: 10.3390/ijms24119687 PMID: 37298637
  26. Benej, M.; Pastorekova, S.; Pastorek, J. Carbonic anhydrase IX: Regulation and role in cancer. Subcell. Biochem., 2014, 75, 199-219. doi: 10.1007/978-94-007-7359-2_11 PMID: 24146381
  27. Potter, C.; Harris, A.L. Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle, 2004, 3(2), 159-162. doi: 10.4161/cc.3.2.618 PMID: 14712082
  28. Becker, H.M. Carbonic anhydrase IX and acid transport in cancer. Br. J. Cancer, 2020, 122(2), 157-167. doi: 10.1038/s41416-019-0642-z PMID: 31819195
  29. Venkateswaran, G.; Dedhar, S. Interplay of carbonic anhydrase IX with amino acid and acid/base transporters in the hypoxic tumor microenvironment. Front. Cell Dev. Biol., 2020, 8602668 doi: 10.3389/fcell.2020.602668 PMID: 33240897
  30. Robertson, N.; Potter, C.; Harris, A.L. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res., 2004, 64(17), 6160-6165. doi: 10.1158/0008-5472.CAN-03-2224 PMID: 15342400
  31. Kaluz, S.; Kaluzová, M.; Liao, S.Y.; Lerman, M.; Stanbridge, E.J. Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show? Biochim. Biophys. Acta, 2009, 1795(2), 162-172. PMID: 19344680
  32. Ivanov, S.; Liao, S.Y.; Ivanova, A.; Danilkovitch-Miagkova, A.; Tarasova, N.; Weirich, G.; Merrill, M.J.; Proescholdt, M.A.; Oldfield, E.H.; Lee, J.; Zavada, J.; Waheed, A.; Sly, W.; Lerman, M.I.; Stanbridge, E.J. Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am. J. Pathol., 2001, 158(3), 905-919. doi: 10.1016/S0002-9440(10)64038-2 PMID: 11238039
  33. Mucaj, V.; Shay, J.E.S.; Simon, M.C. Effects of hypoxia and HIFs on cancer metabolism. Int. J. Hematol., 2012, 95(5), 464-470. doi: 10.1007/s12185-012-1070-5 PMID: 22539362
  34. Temiz, E.; Koyuncu, I.; Durgun, M.; Caglayan, M.; Gonel, A.; Güler, E.M.; Kocyigit, A.; Supuran, C.T. Inhibition of carbonic anhydrase IX promotes apoptosis through intracellular pH level alterations in cervical cancer cells. Int. J. Mol. Sci., 2021, 22(11), 6098. doi: 10.3390/ijms22116098 PMID: 34198834
  35. Lee, S.H.; McIntyre, D.; Honess, D.; Hulikova, A.; Pacheco-Torres, J.; Cerdán, S.; Swietach, P.; Harris, A.L.; Griffiths, J.R. Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. Br. J. Cancer, 2018, 119(5), 622-630. doi: 10.1038/s41416-018-0216-5 PMID: 30206370
  36. 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. doi: 10.1007/s10555-019-09799-0 PMID: 31076951
  37. Parkkila, S.; Parkkila, A.K.; Saarnio, J.; Kivelä, J.; Karttunen, T.J.; Kaunisto, K.; Waheed, A.; Sly, W.S.; Türeci, Ö.; Virtanen, I.; Rajaniemi, H. Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J. Histochem. Cytochem., 2000, 48(12), 1601-1608. doi: 10.1177/002215540004801203 PMID: 11101628
  38. Ilie, M.I.; Hofman, V.; Ortholan, C.; Ammadi, R.E.; Bonnetaud, C.; Havet, K.; Venissac, N.; Mouroux, J.; Mazure, N.M.; Pouysségur, J.; Hofman, P. Overexpression of carbonic anhydrase XII in tissues from resectable non‐small cell lung cancers is a biomarker of good prognosis. Int. J. Cancer, 2011, 128(7), 1614-1623. doi: 10.1002/ijc.25491 PMID: 20521252
  39. von Neubeck, B.; Gondi, G.; Riganti, C.; Pan, C.; Parra Damas, A.; Scherb, H.; Ertürk, A.; Zeidler, R. An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo. Int. J. Cancer, 2018, 143(8), 2065-2075. doi: 10.1002/ijc.31607 PMID: 29786141
  40. Li, Y.; Lei, B.; Zou, J.; Wang, W.; Chen, A.; Zhang, J.; Fu, Y.; Li, Z. High expression of carbonic anhydrase 12 (CA12) is associated with good prognosis in breast cancer. Neoplasma, 2019, 66(3), 420-426. doi: 10.4149/neo_2018_180819N624 PMID: 30784287
  41. Hynninen, P.; Vaskivuo, L.; Saarnio, J.; Haapasalo, H.; Kivelä, J.; Pastoreková, S.; Pastorek, J.; Waheed, A.; Sly, W.S.; Puistola, U.; Parkkila, S. Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumours. Histopathology, 2006, 49(6), 594-602. doi: 10.1111/j.1365-2559.2006.02523.x PMID: 17163844
  42. Supuran, C.T. Carbonic anhydrase inhibitors: An update on experimental agents for the treatment and imaging of hypoxic tumors. Expert Opin. Investig. Drugs, 2021, 30(12), 1197-1208. doi: 10.1080/13543784.2021.2014813 PMID: 34865569
  43. Nerella, S.G.; Thacker, P.S.; Arifuddin, M.; Supuran, C.T. Tumor associated carbonic anhydrase inhibitors: Rational approaches, design strategies, structure activity relationship and mechanistic insights. Eur. J. Med. Chem. Rep., 2024, 10100131 doi: 10.1016/j.ejmcr.2024.100131
  44. Supuran, C.T. Targeting carbonic anhydrases for the management of hypoxic metastatic tumors. Expert Opin. Ther. Pat., 2023, 33(11), 701-720. doi: 10.1080/13543776.2023.2245971 PMID: 37545058
  45. Chen, F.; Licarete, E.; Wu, X.; Petrusca, D.; Maguire, C.; Jacobsen, M.; Colter, A.; Sandusky, G.E.; Czader, M.; Capitano, M.L.; Ropa, J.P.; Boswell, H.S.; Carta, F.; Supuran, C.T.; Parkin, B.; Fishel, M.L.; Konig, H. Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions. J. Cell. Mol. Med., 2021, 25(24), 11039-11052. doi: 10.1111/jcmm.17027 PMID: 34791807
  46. Krasavin, M.; Kalinin, S.; Sharonova, T.; Supuran, C.T. Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 1555-1561. doi: 10.1080/14756366.2020.1801674 PMID: 32746643
  47. McDonald, P.C.; Chafe, S.C.; Supuran, C.T.; Dedhar, S. Cancer therapeutic targeting of hypoxia induced carbonic anhydrase IX: From bench to bedside. Cancers, 2022, 14(14), 3297. doi: 10.3390/cancers14143297 PMID: 35884358
  48. Supuran, C.T. Experimental carbonic anhydrase inhibitors for the treatment of hypoxic tumors. J. Exp. Pharmacol., 2020, 12, 603-617. doi: 10.2147/JEP.S265620 PMID: 33364855
  49. Pastorek, J.; Pastorekova, S.; Zatovicova, M. Cancer-associated carbonic anhydrases and their inhibition. Curr. Pharm. Des., 2008, 14(7), 685-698. doi: 10.2174/138161208783877893 PMID: 18336315
  50. Singh, S.; Lomelino, C.; Mboge, M.; Frost, S.; McKenna, R. Cancer drug development of carbonic anhydrase inhibitors beyond the active site. Molecules, 2018, 23(5), 1045. doi: 10.3390/molecules23051045 PMID: 29710858
  51. 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. doi: 10.1080/13543784.2018.1548608 PMID: 30426805
  52. Kciuk, M.; Gielecińska, A.; Mujwar, S.; Mojzych, M.; Marciniak, B.; Drozda, R.; Kontek, R. Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 1278-1298. doi: 10.1080/14756366.2022.2052868 PMID: 35506234
  53. Ialongo, D.; Messore, A.; Madia, V.N.; Tudino, V.; Nocentini, A.; Gratteri, P.; Giovannuzzi, S.; Supuran, C.T.; Nicolai, A.; Scarpa, S.; Taurone, S.; Camarda, M.; Artico, M.; Papa, V.; Saccoliti, F.; Scipione, L.; Di Santo, R.; Costi, R. Pyrrolyl and indolyl α-γ-diketo acid XII. Pharmaceuticals, 2023, 16, 188. doi: 10.3390/ph16020188 PMID: 37259337
  54. Liu, L.C.; Xu, W.T.; Wu, X.; Zhao, P.; Lv, Y.L.; Chen, L. Overexpression of carbonic anhydrase II and Ki-67 proteins in prognosis of gastrointestinal stromal tumors. World J. Gastroenterol., 2013, 19(16), 2473-2480. doi: 10.3748/wjg.v19.i16.2473 PMID: 23674848
  55. Viikilä, P.; Kivelä, A.J.; Mustonen, H.; Koskensalo, S.; Waheed, A.; Sly, W.S.; Doisy, E.A.; Pastorek, J.; Pastorekova, S.; Parkkila, S.; Haglund, C. Carbonic anhydrase enzymes II, VII, IX and XII in colorectal carcinomas. World J. Gastroenterol., 2016, 22(36), 8168-8177. doi: 10.3748/wjg.v22.i36.8168 PMID: 27688658
  56. Tachibana, H.; Gi, M.; Kato, M.; Yamano, S.; Fujioka, M.; Kakehashi, A.; Hirayama, Y.; Koyama, Y.; Tamada, S.; Nakatani, T.; Wanibuchi, H. Carbonic anhydrase 2 is a novel invasion‐associated factor in urinary bladder cancers. Cancer Sci., 2017, 108(3), 331-337. doi: 10.1111/cas.13143 PMID: 28004470
  57. Supuran, C.T. A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation. Bioorg. Med. Chem. Lett., 2023, 93129411 doi: 10.1016/j.bmcl.2023.129411 PMID: 37507055
  58. Vullo, D.; Carta, F. Mechanisms of action of carbonic anhydrase inhibitors: Zinc binders.In: Carbonic Anhydrases: Biochemistry and Pharmacology of an Evergreen Pharmaceutical Target; Elsevier, 2019, pp. 187-222. doi: 10.1016/B978-0-12-816476-1.00009-5
  59. Carta, F.; Supuran, C.T.; Scozzafava, A. Sulfonamides and their isosters as carbonic anhydrase inhibitors. Future Med. Chem., 2014, 6(10), 1149-1165. doi: 10.4155/fmc.14.68 PMID: 25078135
  60. Guedes, G.B.; Karan, A.; Mayer, H.R.; Shields, M.B. Evaluation of adverse events in self-reported sulfa-allergic patients using topical carbonic anhydrase inhibitors. J. Ocul. Pharmacol. Ther., 2013, 29(5), 456-461. doi: 10.1089/jop.2012.0123 PMID: 23445203
  61. Kumar, A.; Siwach, K.; Supuran, C.T.; Sharma, P.K. A decade of tail-approach based design of selective as well as potent tumor associated carbonic anhydrase inhibitors. Bioorg. Chem., 2022, 126105920 doi: 10.1016/j.bioorg.2022.105920 PMID: 35671645
  62. Tanpure, R.P.; Ren, B.; Peat, T.S.; Bornaghi, L.F.; Vullo, D.; Supuran, C.T.; Poulsen, S.A. Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site. J. Med. Chem., 2015, 58(3), 1494-1501. doi: 10.1021/jm501798g PMID: 25581127
  63. Stams, T.; Christianson, D.W. X-ray crystallographic studies of mammalian carbonic anhydrase isozymes. EXS, 2000, 90(90), 159-174. doi: 10.1007/978-3-0348-8446-4_9 PMID: 11268515
  64. Carta, F.; Vullo, D.; Osman, S.M.; AlOthman, Z.; Supuran, C.T. Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs. Bioorg. Med. Chem., 2017, 25(9), 2569-2576. doi: 10.1016/j.bmc.2017.03.027 PMID: 28347633
  65. Pacchiano, F.; Carta, F.; McDonald, P.C.; Lou, Y.; Vullo, D.; Scozzafava, A.; Dedhar, S.; Supuran, C.T. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem., 2011, 54(6), 1896-1902. doi: 10.1021/jm101541x PMID: 21361354
  66. Eloranta, K.; Pihlajoki, M.; Liljeström, E.; Nousiainen, R.; Soini, T.; Lohi, J.; Cairo, S.; Wilson, D.B.; Parkkila, S.; Heikinheimo, M. SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration. Front. Oncol., 2023, 131118268 doi: 10.3389/fonc.2023.1118268 PMID: 36776327
  67. Huo, Z.; Bilang, R.; Supuran, C.T.; von der Weid, N.; Bruder, E.; Holland-Cunz, S.; Martin, I.; Muraro, M.G.; Gros, S.J. Perfusion- based bioreactor culture and isothermal microcalorimetry for preclinical drug testing with the carbonic anhydrase inhibitor SLC-0111 in patient-derived neuroblastoma. Int. J. Mol. Sci., 2022, 23(6), 3128. doi: 10.3390/ijms23063128 PMID: 35328549
  68. Andreucci, E.; Ruzzolini, J.; Peppicelli, S.; Bianchini, F.; Laurenzana, A.; Carta, F.; Supuran, C.T.; Calorini, L. The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 117-123. doi: 10.1080/14756366.2018.1532419 PMID: 30362384
  69. Lomelino, C.; Supuran, C.; McKenna, R. Non-classical inhibition of carbonic anhydrase. Int. J. Mol. Sci., 2016, 17(7), 1150. doi: 10.3390/ijms17071150 PMID: 27438828
  70. Fuentes-Aguilar, A.; Merino-Montiel, P.; Montiel-Smith, S.; Meza-Reyes, S.; Vega-Báez, J.L.; Puerta, A.; Fernandes, M.X.; Padrón, J.M.; Petreni, A.; Nocentini, A.; Supuran, C.T.; López, Ó.; Fernández-Bolaños, J.G. 2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 168-177. doi: 10.1080/14756366.2021.1998026 PMID: 34894971
  71. Arrighi, G.; Puerta, A.; Petrini, A.; Hicke, F.J.; Nocentini, A.; Fernandes, M.X.; Padrón, J.M.; Supuran, C.T.; Fernández-Bolaños, J.G.; López, Ó. Squaramide-tethered sulfonamides and coumarins: Synthesis, inhibition of tumor-associated CAs IX and XII and docking simulations. Int. J. Mol. Sci., 2022, 23(14), 7685. doi: 10.3390/ijms23147685 PMID: 35887037
  72. Supuran, C.T. Coumarin carbonic anhydrase inhibitors from natural sources. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 1462-1470. doi: 10.1080/14756366.2020.1788009 PMID: 32779543
  73. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C.T. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J. Med. Chem., 2010, 53(1), 335-344. doi: 10.1021/jm901287j PMID: 19911821
  74. Maresca, A.; Temperini, C.; Vu, H.; Pham, N.B.; Poulsen, S.A.; Scozzafava, A.; Quinn, R.J.; Supuran, C.T. Non-zinc mediated inhibition of carbonic anhydrases: Coumarins are a new class of suicide inhibitors. J. Am. Chem. Soc., 2009, 131(8), 3057-3062. doi: 10.1021/ja809683v PMID: 19206230
  75. Eldehna, W.M.; Taghour, M.S.; Al-Warhi, T.; Nocentini, A.; Elbadawi, M.M.; Mahdy, H.A.; Abdelrahman, M.A.; Alotaibi, O.J.; Aljaeed, N.; Elimam, D.M.; Afarinkia, K.; Abdel-Aziz, H.A.; Supuran, C.T. Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 531-541. doi: 10.1080/14756366.2021.2024528 PMID: 34991416
  76. M Ghouse,, S.; Bahatam, K.; Angeli, A.; Pawar, G; Chinchilli, K.K.; Yaddanapudi, V.M.; Mohammed, A.; Supuran, C.T; Nanduri, S. Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII. J. Enzyme Inhib. Med. Chem., 2023, 38(1)2185760 doi: 10.1080/14756366.2023.2185760 PMID: 36876597
  77. Thacker, P.S.; Angeli, A.; Argulwar, O.S.; Tiwari, P.L.; Arifuddin, M.; Supuran, C.T. Design, synthesis and biological evaluation of coumarin linked 1,2,4-oxadiazoles as selective carbonic anhydrase IX and XII inhibitors. Bioorg. Chem., 2020, 98103739 doi: 10.1016/j.bioorg.2020.103739 PMID: 32193032
  78. De Luca, L.; Mancuso, F.; Ferro, S.; Buemi, M.R.; Angeli, A.; Del Prete, S.; Capasso, C.; Supuran, C.T.; Gitto, R. Inhibitory effects and structural insights for a novel series of coumarin-based compounds that selectively target human CA IX and CA XII carbonic anhydrases. Eur. J. Med. Chem., 2018, 143, 276-282. doi: 10.1016/j.ejmech.2017.11.061 PMID: 29197732
  79. Al-Warhi, T.; Sabt, A.; Elkaeed, E.B.; Eldehna, W.M. Recent advancements of coumarin-based anticancer agents: An up-to-date review. Bioorg. Chem., 2020, 103104163 doi: 10.1016/j.bioorg.2020.104163 PMID: 32890989
  80. Stefanachi, A.; Leonetti, F.; Pisani, L.; Catto, M.; Carotti, A. Coumarin: A natural, privileged and versatile scaffold for bioactive compounds. Molecules, 2018, 23(2), 250. doi: 10.3390/molecules23020250 PMID: 29382051
  81. Oukoloff, K.; Lucero, B.; Francisco, K.R.; Brunden, K.R.; Ballatore, C. 1,2,4-Triazolo1,5-apyrimidines in drug design. Eur. J. Med. Chem., 2019, 165, 332-346. doi: 10.1016/j.ejmech.2019.01.027 PMID: 30703745
  82. Dai, X.J.; Xue, L.P.; Ji, S.K.; Zhou, Y.; Gao, Y.; Zheng, Y.C.; Liu, H.M.; Liu, H.M. Triazole-fused pyrimidines in target-based anticancer drug discovery. Eur. J. Med. Chem., 2023, 249115101 doi: 10.1016/j.ejmech.2023.115101 PMID: 36724635
  83. Maresta, A.; Balducelli, M.; Cantini, L.; Casari, A.; Chioin, R.; Fabbri, M.; Fontanelli, A.; Monici Preti, P.A.; Repetto, S.; De Servi, S. Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Results of the randomized, double-blind STARC study. Studio Trapidil versus Aspirin nella Restenosi Coronarica. Circulation, 1994, 90(6), 2710-2715. doi: 10.1161/01.CIR.90.6.2710 PMID: 7994812
  84. Said, M.A.; Eldehna, W.M.; Nocentini, A.; Bonardi, A.; Fahim, S.H.; Bua, S.; Soliman, D.H.; Abdel-Aziz, H.A.; Gratteri, P.; Abou-Seri, S.M.; Supuran, C.T. Synthesis, biological and molecular dynamics investigations with a series of triazolopyrimidine/triazole-based benzenesulfonamides as novel carbonic anhydrase inhibitors. Eur. J. Med. Chem., 2020, 185111843 doi: 10.1016/j.ejmech.2019.111843 PMID: 31718943
  85. Romagnoli, R.; De Ventura, T.; Manfredini, S.; Baldini, E.; Supuran, C.T.; Nocentini, A.; Brancale, A.; Varricchio, C.; Bortolozzi, R.; Manfreda, L.; Viola, G. Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold. J. Enzyme Inhib. Med. Chem., 2023, 38(1)2270180 doi: 10.1080/14756366.2023.2270180 PMID: 37850364
  86. Oliva, P.; Romagnoli, R.; Cacciari, B.; Manfredini, S.; Padroni, C.; Brancale, A.; Ferla, S.; Hamel, E.; Corallo, D.; Aveic, S.; Milan, N.; Mariotto, E.; Viola, G.; Bortolozzi, R. Synthesis and biological evaluation of highly active 7-anilino triazolopyrimidines as potent antimicrotubule agents. Pharmaceutics, 2022, 14(6), 1191. doi: 10.3390/pharmaceutics14061191 PMID: 35745764
  87. Romagnoli, R.; Oliva, P.; Prencipe, F.; Manfredini, S.; Budassi, F.; Brancale, A.; Ferla, S.; Hamel, E.; Corallo, D.; Aveic, S.; Manfreda, L.; Mariotto, E.; Bortolozzi, R.; Viola, G. Design, synthesis and biological investigation of 2-anilino triazolopyrimidines as tubulin polymerization inhibitors with anticancer activities. Pharmaceuticals, 2022, 15(8), 1031. doi: 10.3390/ph15081031 PMID: 36015179
  88. Tars, K.; Vullo, D.; Kazaks, A.; Leitans, J.; Lends, A.; Grandane, A.; Zalubovskis, R.; Scozzafava, A.; Supuran, C.T. Sulfocoumarins (1,2-benzoxathiine-2,2-dioxides): A class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases. J. Med. Chem., 2013, 56(1), 293-300. doi: 10.1021/jm301625s PMID: 23241068
  89. 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. doi: 10.1016/S0021-9258(18)62326-9 PMID: 4994926
  90. Pistollato, F.; Abbadi, S.; Rampazzo, E.; Persano, L.; Della, P.A.; Frasson, C.; Sarto, E.; Scienza, R.; D’avella, D.; Basso, G. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells, 2010, 28(5), 851-862. doi: 10.1002/stem.415 PMID: 20309962
  91. Onnis, V. Special issue “Novel anti-proliferative agents”. Pharmaceuticals, 2023, 16(10), 1437. doi: 10.3390/ph16101437 PMID: 37895908

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