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Current Organic Synthesis

Editor-in-Chief

ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Research Article

Tetra-azolium Salts Induce Significant Cytotoxicity in Human Colon Cancer Cells In vitro

Author(s): Muhammad Ashraf, Amna Kamal, Ejaz Ahmed, Haq Nawaz Bhatti, Muhammad Arshad and Muhammad Adnan Iqbal*

Volume 21, Issue 8, 2024

Published on: 23 November, 2023

Page: [1075 - 1080] Pages: 6

DOI: 10.2174/1570179421666230824151219

Price: $65

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Abstract

Background: Azolium salts are the organic salts used as stable precursors for generating N-Heterocyclic Carbenes and their metal complexes. Azolium salts have also been reported to have significant biological potential. Hence, in the current study, four tetra-dentate azolium salts were derived from bis-azolium salts by a new synthetic strategy.

Methods: The tetra azolium salts have been synthesized by reacting the imidazole or methyl imidazole with dibromo xylene (meta, para)/ 1-bromo methyl imidazole or dibromo ethane resulting in the mono or bis azolium salts namely I-IV. V-VII have been obtained by reacting I with II-IV, resulting in the tetra azolium salts. Each product was analyzed by various analytical techniques, i.e., microanalysis, FT-IR, and NMR (1H & 13C). Salts V-VII were evaluated for their antiproliferative effect against human colon cancer cells (HCT-116) using MTT assay.

Results: Four chemical shifts for acidic protons between 8.5-9.5 δ ppm in 1H NMR and resonance of respective carbons around 136-146 δ ppm in 13C NMR indicated the successful synthesis of tetra azolium salts. Salt V showed the highest IC50 value, 24.8 μM among all synthesized compounds.

Conclusion: Tetra-azolium salts may play a better cytotoxicity effect compared to mono-, bi-& tri-azolium salts.

Keywords: Tetra-nuclear, azolium salts, NHC, anti-cancer, HCT-116, cytotoxicity, IC50.

Graphical Abstract
[1]
(a) Hackenberg, F.M. Carbene-metal complexes as anticancer and antibacterial drug candidates; University College Dublin, Ireland, 2013. ;
(b) Kamal, A.; Iqbal, M.A.; Bhatti, H.N. Therapeutic applications of selenium-derived compounds. Rev. Inorg. Chem., 2018, 38(2), 49-76.
[2]
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016, 388(10053), 1659-1724.
[http://dx.doi.org/10.1016/S0140-6736(16)31679-8] [PMID: 27733284]
[3]
Galema, H.A.; Meijer, R.P.J.; Lauwerends, L.J.; Verhoef, C.; Burggraaf, J.; Vahrmeijer, A.L.; Hutteman, M.; Keereweer, S.; Hilling, D.E. Fluorescence-guided surgery in colorectal cancer; A review on clinical results and future perspectives. Eur. J. Surg. Oncol., 2022, 48(4), 810-821.
[http://dx.doi.org/10.1016/j.ejso.2021.10.005] [PMID: 34657780]
[4]
(a) Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.;
(b) Zhao, Q.; Wang, F.; Chen, Y.X.; Chen, S.; Yao, Y.C.; Zeng, Z.L.; Jiang, T.J.; Wang, Y.N.; Wu, C.Y.; Jing, Y. Comprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer. Nat. Commun., 2022, 13(1), 2342.
[5]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[6]
(a) Plummer, M.; de Martel, C.; Vignat, J.; Ferlay, J.; Bray, F.; Franceschi, S. Global burden of cancers attributable to infections in 2012: A synthetic analysis. The Lancet Global Health., 2016, 4(9), 609-616.;
(b) Kawai, K.; Okada, J.; Nakae, M.; Tsujimura, T.; Karuo, Y.; Tarui, A.; Sato, K.; Yamashita, S.; Kataoka, M.; Omote, M. Discovery of benzyloxyphenyl-and phenethylphenyl-imidazole derivatives as a new class of ante–drug type boosters. Bioorganic & Medicinal Chemistry Letters, 2022, 72, 128868.;
(c) Deng, C.; Yan, H.; Wang, J.; Liu, B.S.; Liu, K.; Shi, Y.M. The anti-HIV potential of imidazole, oxazole and thiazole hybrids: A mini-review. Arab. J. Chem., 2022, 104242.;
(d) Slassi, S.; Aarjane, M.; Amine, A. Novel triazole derivatives possessing imidazole: Synthesis, spectroscopic characterization (FT-IR, NMR, UV–Vis), DFT studies and antibacterial in vitro evaluation. J. Mol. Struct., 2023, 1276, 134788.
[7]
(a) Andrei, G.Ş.; Andrei, B.F.; Roxana, P.R. Imidazole derivatives and their antibacterial activity-a mini-review. Mini Rev. Med. Chem., 2021, 21(11), 1380-1392.;
(b) Alghamdi, S.S.; Suliman, R.S.; Almutairi, K.; Kahtani, K.; Aljatli, D. Imidazole as a promising medicinal scaffold: Current status and future direction. Drug Des. Devel. Ther., 2021, 3289-3312.;
(c) Zheng, X.; Ma, Z.; Zhang, D. Synthesis of imidazole-based medicinal molecules utilizing the van leusen imidazole synthesis. Pharmaceuticals, 2020, 13(3), 37.;
(d) Rulhania, S.; Kumar, S.; Nehra, B.; Gupta, G.; Monga, V. An insight into the medicinal perspective of synthetic analogs of imidazole. J. Mol. Struct., 2020, 1232, 129982.
[8]
(a) Rossi, R.; Ciofalo, M. An updated review on the synthesis and antibacterial activity of molecular hybrids and conjugates bearing imidazole moiety. Molecules., 2020, 25(21), 5133.;
(b) Li, C.G.; Chai, Y.M.; Chai, L.Q.; Xu, L.Y. Novel zinc (II) and nickel (II) complexes of a quinazoline‐based ligand with an imidazole ring: Synthesis, spectroscopic property, antibacterial activities, time‐dependent density functional theory calculations and Hirshfeld surface analysis. Appl. Organomet. Chem., 2022, 36(5), e6622.;
(c) Eftekhari, S.; Foroughifar, N.; Hallajian, S.; Khajeh-Amiri, A. Green Synthesis of Some Novel Imidazole Schiff base Derivatives Under Microwave Irradiation/Reflux Conditions and Evaluations of the Antibacterial Activity. Curr. Microw. Chem., 2020, 7(3), 207-215.
[9]
(a) Yardimci, B.K. Imidazole antifungals: A review of their action mechanisms on cancerous cells. Int. J. Second. Metab., 2020, 7(3), 139-159.;
(b) Zhang, j.; Sun, J.; Liu, Y.; Yu, J.; Guo, X. Immobilized cellulose-based Chiralpak IC chiral stationary phase for Enantioseparation of eight imidazole antifungal drugs in normal-phase, polar organic phase and reversed-phase conditions using high-performance liquid chromatography. Chromatographia, 2019, 82, 649-660.;
(c) Tippannanavar, M.; Verma, A.; Kumar, A.; Gogoi, R.; Kundu, A.; Patanjali, N. Preparation of nanofungicides based on imidazole drugs and their antifungal evaluation. J. Agric. Food Chem., 2020, 68, 16-4566.
[10]
Aruchamy, B.; Drago, C.; Russo, V.; Pitari, G.M.; Ramani, P.; Aneesh, T.P.; Benny, S.; Vishnu, V.R. Imidazole-pyridine hybrids as potent anti-cancer agents. Eur. J. Pharm. Sci., 2023, 180, 106323.
[http://dx.doi.org/10.1016/j.ejps.2022.106323] [PMID: 36336277]
[11]
(a) Adnan Iqbal, M.; Haque, A.; A Ahamed, S.; Fatemeh Jafari, S.; Khadeer Ahamed, M.; MS Abdul Majid, A. Crystal structures and cytotoxicity of ortho-xylene linked bis-benzimidazolium salts. Med. Chem., 2015, 11(5), 473-481.
[PMID: 18032039];
(b) Habib, A.; Iqbal, M.A.; Bhatti, H.N.; Shahid, M. Effect of ring substitution on synthesis of benzimidazolium salts and their silver (I) complexes: characterization, electrochemical studies and evaluation of anticancer potential. Transit. Met. Chem., 2019, 44, 431-443.;
(c) Emami, S.; Foroumadi, A.; Falahati, M.; Lotfali, E.; Rajabalian, S.; Ebrahimi, S.A.; Farahyar, S.; Shafiee, A. 2-Hydroxyphenacyl azoles and related azolium derivatives as antifungal agents. Bioorganic Med. Chem. Lett., 2008, 18(1), 141-146.
[12]
Ashraf, R.; Sarfraz, A.; Taskin-Tok, T.; Iqbal, M.J.; Iqbal, M.A.; Iqbal, J.; Bhatti, H.N.; El-Naggar, M.; Akram, S.; Murshed, M.N.; El Sayed, M.E.; Samir, A. Synthesis, molecular docking and anticancer potential of azolium based salts and their silver complexes: DNA/BSA interaction studies and cell cycle analysis. J. Mol. Liq., 2023, 369, 120921.
[http://dx.doi.org/10.1016/j.molliq.2022.120921]
[13]
Riaz, A.; Iqbal, M.A.; Bhatti, H.N.; Shahid, M. Synthesis of sandwich type acyclic tetra-nuclear silver(I)- N -heterocyclic carbene complexes for wound healing applications. Z. Naturforsch. C J. Biosci., 2020, 75(9-10), 369-376.
[http://dx.doi.org/10.1515/znc-2020-0069] [PMID: 32589611]
[14]
(a) Kamal, A.; Iqbal, M.A.; Bhatti, H.N.; Ghaffar, A. Cytotoxic, thrombolytic and antibacterial evaluation of synthesized substituted and un-substituted selenium-n-heterocyclic carbene adducts. J. Chem. Soc. Pak., 2023, 45(128)
[http://dx.doi.org/10.1007/s00044-022-02942-7];
(b) Hayat, K.; Shkeel, M.; Iqbal, M.A.; Quah, C.K.; Wong, Q.A.; Nazari, M.; Ahamed, M.B.K.; Hameed, S. O-Halogen-substituted arene linked selenium-N-heterocyclic carbene compounds induce significant cytotoxicity: Crystal structures and molecular docking studies. J. Organomet. Chem., 2023, 985, 122593.;
(c) Nadeem, R.Y.; Yaqoob, M.; Yam, W.; Haque, R.A.; Iqbal, M.A. Synthesis, characterization and biological evaluation of Bis-benzimidazolium salts and their silver(I)-N-heterocyclic carbene complexes. Med. Chem. Res., 2022, 31(10), 1783-1791.
[15]
Kamal, A.; Nazari V, M.; Yaseen, M.; Iqbal, M.A.; Ahamed, M.B.K.; Majid, A.S.A.; Bhatti, H.N. Green synthesis of selenium-N-heterocyclic carbene compounds: Evaluation of antimicrobial and anticancer potential. Bioorg. Chem., 2019, 90, 103042.
[http://dx.doi.org/10.1016/j.bioorg.2019.103042] [PMID: 31226469]
[16]
Iqbal, M.A.; Haque, R.A.; Ng, W.C.; Hassan, L.E.H.; Majid, A.M.S.A.; Razali, M.R. Green synthesis of mono- and di-selenium-N-heterocyclic carbene adducts: Characterizations, crystal structures and pro-apoptotic activities against human colorectal cancer. J. Organomet. Chem., 2016, 801, 130-138.
[http://dx.doi.org/10.1016/j.jorganchem.2015.10.023]
[17]
Fatima, T.; Haque, R.A.; Iqbal, M.A.; Ahmad, A.; Hassan, L.E.A.; Taleb-Agha, M.; Ahamed, M.B.K.; Majid, A.M.S.A.; Razali, M.R. Tetra N -heterocyclic carbene dinuclear silver(I) complexes as potential anticancer agents: Synthesis and in vitro anticancer studies. J. Organomet. Chem., 2017, 853, 122-135.
[http://dx.doi.org/10.1016/j.jorganchem.2017.10.045]
[18]
Iqbal, M.A.; Haque, R.A.; Nasri, S.F.; Majid, A.M.S.A.; Ahamed, M.B.K.; Farsi, E.; Fatima, T. Potential of silver against human colon cancer: (synthesis, characterization and crystal structures of xylyl (Ortho, meta, & Para) linked bis-benzimidazolium salts and Ag(I)-NHC complexes: In vitro anticancer studies). Chem. Cent. J., 2013, 7(1), 27.
[http://dx.doi.org/10.1186/1752-153X-7-27] [PMID: 23391345]
[19]
Fatima, T.; Haque, R.A.; Razali, M.R.; Ahmad, A.; Asif, M.; Khadeer Ahamed, M.B.; Abdul Majid, A.M.S. Effect of lipophilicity of wingtip groups on the anticancer potential of mono N-heterocyclic carbene silver(I) complexes: Synthesis, crystal structures and in vitro anticancer study. Appl. Organomet. Chem., 2017, 31(10), e3735.
[http://dx.doi.org/10.1002/aoc.3735]
[20]
Asif, M.; Iqbal, M.A.; Hussein, M.A.; Oon, C.E.; Haque, R.A.; Khadeer Ahamed, M.B.; Abdul Majid, A.S.; Abdul Majid, A.M.S. Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)– N -Heterocyclic carbene (NHC) complexes. Eur. J. Med. Chem., 2016, 108, 177-187.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.034] [PMID: 26649905]
[21]
Kamal, A.; Iqbal, M.A.; Bhatti, H.N.; Ghaffar, A. Selenium- N -heterocyclic carbene (Se-NHC) complexes with higher aromaticity inhibit microbes: synthesis, structure, and biological potential. J. Coord. Chem., 2022, 75(11-14), 1915-1928.
[http://dx.doi.org/10.1080/00958972.2022.2101921]
[22]
Iqbal, M.A.; Haque, R.A.; Ahamed, M.B.K.; Majid, A.M.S.A.; Al-Rawi, S.S. Synthesis and anticancer activity of para-xylyl linked bis-benzimidazolium salts and respective Ag(I) N-heterocyclic carbene complexes. Med. Chem. Res., 2013, 22(5), 2455-2466.
[http://dx.doi.org/10.1007/s00044-012-0240-6]
[23]
(a) Habib, A.; Iqbal, M.A.; Bhatti, H.N.; Kamal, A.; Kamal, S. Synthesis of alkyl/aryl linked binuclear silver (I)-N-Heterocyclic carbene complexes and evaluation of their antimicrobial, hemolytic and thrombolytic potential. Inorg. Chem. Commun., 2020, 111, 107670.;
(b) Naz, N.; Saqib, S.; Ashraf, R.; Majeed, M.L.; Iqbal, M.A. Synthesis of new organoselenium compounds: characterization and biological studies. Maced. J. Chem. Chem., 2020, 39(1), 1-10.;
(c) Haque, R.A.; Iqbal, M.A.; Mohamad, F.; Razali, M.R. Antibacterial and DNA cleavage activity of carbonyl functionalized N-heterocyclic carbene-silver (I) and selenium compounds. J. Mol. Struct., 2018, 1155, 362-370.;
(d) Iqbal, M.A.; Haque, R.A.; Budagumpi, S.; Ahamed, M.B.K.; Majid, A.M.A. Short metal–metal separations and in vitro anticancer studies of a new dinuclear silver (I)-N-heterocyclic carbene complex of para-xylyl-linked bis-benzimidazolium salt. Inorg. Chem. Commun., 2018, 28, 64-69.
[24]
(a) Chiang, E.; Bostwick, D.; Waters, D. Selenium form-dependent anti-carcinogenesis: preferential elimination of oxidant-damaged prostate cancer cell populations by methylseleninic acid is not shared by selenite. Vitam. Miner, 2015, 4(1), 2376-1318.;
(b) Verlinden, k.; Buhl, h.; Frank, W.; Ganter, C.; Frank, W.; Frank, W. Determining the ligand properties of N‐heterocyclic carbenes from 77Se NMR parameters. Eur. J. Inorg. Chem., 2015, 2015(14), 2416-2425.
[25]
Ivanenkov, Y.A.; Veselov, M.S.; Rezekin, I.G.; Skvortsov, D.A.; Sandulenko, Y.B.; Polyakova, M.V.; Bezrukov, D.S.; Vasilevsky, S.V.; Kukushkin, M.E.; Moiseeva, A.A.; Finko, A.V.; Koteliansky, V.E.; Klyachko, N.L.; Filatova, L.A.; Beloglazkina, E.K.; Zyk, N.V.; Majouga, A.G. Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives. Bioorg. Med. Chem., 2016, 24(4), 802-811.
[http://dx.doi.org/10.1016/j.bmc.2015.12.050] [PMID: 26780833]

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