Synthesis and anticancer activity of new benzensulfonamides incorporating s-triazines as cyclic linkers for inhibition of carbonic anhydrase IX.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Antineoplastic Agents*/pharmacology ; Breast Neoplasms*/drug therapy; Antigens, Neoplasm/metabolism ; Carbonic Anhydrase IX/metabolism ; Carbonic Anhydrase Inhibitors/pharmacology ; Caspases/metabolism ; Female ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Structure-Activity Relationship ; Sulfonamides ; Triazines/pharmacology ; Benzenesulfonamides

Limited presence of hCA IX in normal physiological tissues and their overexpression only in solid hypoxic tumors made this isoform excellent possible target for developing new anticancer agents. We reported designing and synthesis of two novel series of benzenesulfonamides derivatives as hCA IX inhibitors bearing rigid cyclic linkers (1,3,5-dihydrotriazine in series A and 1,3,5-triazine in series B) in replace of traditional linear linkers. Also, novel cyanoethenyl spacer was assembled next to the 1,3,5-triazine linker in series B. Target compounds of series (A) and (B) were screened against four hCA isoforms. Human CA IX efficiently inhibited in series (A) by compound 5a (K I  = 134.8 nM). Meanwhile, in series (B) the most active inhibitor was 12i (K I  = 38.8 nM). US-NCI protocol was followed to evaluate the anticancer activity of target compounds against panel of sixty cancer cell lines. Compound 12d, exposed the best activity towards breast cancer (MDA-MB-468) with GI% = 62%. The most active analogues, 12d and 12i were further screened for in vitro cytotoxic activity under hypoxic condition against breast cancer (MDA-MB-468) (IC 50  = 3.99 ± 0.21 and 1.48 ± 0.08 µM, respectively) and leukemia (CCRF-CM) cell line (IC 50  = 4.51 ± 0.24 and 9.83 ± 0.52 µM, respectively). In addition, 12d arrested breast cancer MDA-MB-468 cell cycle in G0-G1 and S phases and induced its apoptosis which indicated by increasing the level of cleaved caspases 3 and 9. Molecular docking was performed for selected analogues to understand their biological alterations. This study revealed that insertion of 1,3,5-triazines as cyclic linkers enhanced the significant anticancer and hCA IX inhibition activity of benzenesulfonamides.
(© 2022. The Author(s).)

Eur J Med Chem. 2020 Mar 1;189:112019. (PMID: 31972394)
J Med Chem. 2016 Dec 8;59(23):10692-10704. (PMID: 27933963)
Bioorg Med Chem. 2017 Apr 1;25(7):2210-2217. (PMID: 28256371)
J Med Chem. 2020 Mar 26;63(6):3317-3326. (PMID: 32031797)
Eur J Med Chem. 2018 Dec 5;160:49-60. (PMID: 30317025)
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16233-8. (PMID: 19805286)
Med Res Rev. 2018 Sep;38(6):1799-1836. (PMID: 29635752)
Int J Mol Sci. 2018 Mar 13;19(3):. (PMID: 29534020)
Bioorg Chem. 2019 Sep;90:103102. (PMID: 31299596)
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1095-1107. (PMID: 29944015)
Med Res Rev. 2020 Nov;40(6):2485-2565. (PMID: 32691504)
Bioorg Chem. 2021 Dec;117:105451. (PMID: 34736137)
Expert Opin Ther Pat. 2018 Oct;28(10):729-740. (PMID: 30074415)
Bioorg Med Chem Lett. 2014 Apr 1;24(7):1776-9. (PMID: 24589511)
J Immunol Methods. 2015 Aug;423:99-103. (PMID: 25975759)
Curr Top Med Chem. 2007;7(9):825-33. (PMID: 17504127)
Bioorg Chem. 2018 Aug;78:290-297. (PMID: 29621641)
Bioorg Med Chem. 2010 Aug 1;18(15):5701-7. (PMID: 20615714)
Int J Biol Macromol. 2019 Oct 1;138:359-369. (PMID: 31323265)
Chem Rev. 2012 Aug 8;112(8):4421-68. (PMID: 22607219)
Leukemia. 2021 Jan;35(1):62-74. (PMID: 32203138)
J Med Chem. 2011 Mar 24;54(6):1896-902. (PMID: 21361354)
Eur J Med Chem. 2021 Jan 1;209:112923. (PMID: 33121862)
J Enzyme Inhib Med Chem. 2013 Apr;28(2):229-30. (PMID: 23379684)
Acta Histochem. 2018 May;120(4):303-311. (PMID: 29606555)
Proteomics Clin Appl. 2015 Apr;9(3-4):396-405. (PMID: 25597284)
J Med Chem. 2017 Mar 9;60(5):1734-1745. (PMID: 28177228)
Bioorg Chem. 2020 Jan;95:103544. (PMID: 31915112)
Biochim Biophys Acta. 2010 Feb;1804(2):404-9. (PMID: 19679200)
J Immunol Methods. 1983 Dec 16;65(1-2):55-63. (PMID: 6606682)
J Enzyme Inhib Med Chem. 2016 Oct;31(5):796-809. (PMID: 26226179)
Eur J Med Chem. 2018 Jan 20;144:544-556. (PMID: 29289880)
Metabolites. 2018 Feb 28;8(1):. (PMID: 29495652)
Bioorg Chem. 2021 May;110:104748. (PMID: 33684714)
Semin Cancer Biol. 2015 Apr;31:52-64. (PMID: 25117006)
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1575-1580. (PMID: 30296852)
Eur J Med Chem. 2021 Apr 15;216:113283. (PMID: 33667848)
Clin Oral Investig. 2021 May;25(5):2555-2568. (PMID: 32918121)
Cell Death Differ. 1999 Feb;6(2):99-104. (PMID: 10200555)
J Enzyme Inhib Med Chem. 2017 Dec;32(1):600-613. (PMID: 28173708)
Nat Rev Drug Discov. 2008 Feb;7(2):168-81. (PMID: 18167490)
J Enzyme Inhib Med Chem. 2018 Dec;33(1):686-700. (PMID: 29560733)
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5428-31. (PMID: 21788136)
Expert Opin Ther Pat. 2018 Oct;28(10):713-721. (PMID: 30175635)
Top Anticancer Res. 2015;5:3-42. (PMID: 30272043)
Bioorg Chem. 2019 Feb;82:117-122. (PMID: 30312866)
Eur J Med Chem. 2019 Jan 15;162:147-160. (PMID: 30445264)
Bioorg Chem. 2018 Dec;81:425-432. (PMID: 30219719)
J Biol Chem. 1971 Apr 25;246(8):2561-73. (PMID: 4994926)
Bioorg Med Chem Lett. 2021 Sep 15;48:128249. (PMID: 34237441)
Eur J Med Chem. 2006 Feb;41(2):219-25. (PMID: 16377034)
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5644-7. (PMID: 19716698)
Molecules. 2018 Jul 03;23(7):. (PMID: 29970833)
Metabolites. 2017 Sep 16;7(3):. (PMID: 28926956)
Eur J Med Chem. 2022 Jan 15;228:114008. (PMID: 34871842)
Acta Pol Pharm. 2004 Nov-Dec;61(6):461-6. (PMID: 15794339)
Nat Rev Mol Cell Biol. 2013 Aug;14(8):518-28. (PMID: 23877564)
J Med Chem. 2021 Feb 11;64(3):1713-1724. (PMID: 33523653)
Bioorg Chem. 2018 Dec;81:241-252. (PMID: 30153589)
J Med Chem. 2015 Nov 25;58(22):9004-9. (PMID: 26522624)

0 (Antigens, Neoplasm)
0 (Antineoplastic Agents)
0 (Carbonic Anhydrase Inhibitors)
0 (Sulfonamides)
0 (Triazines)
EC 3.4.22.- (Caspases)
EC 4.2.1.1 (Carbonic Anhydrase IX)

Date Created: 20221006 Date Completed: 20221010 Latest Revision: 20231213

20250114

PMC9537541

10.1038/s41598-022-21024-7

36202955