Unveiling the Full Potential of 2-aryl-1H-phenanthro [9,10-d] imidazoles as Cytotoxic Agents vs AGS, HepG2 and MCF-7 Cell lines

Mohammadi, Mohammad Kazem; Bohluli, Shahab; Javid, Ali; Tavakkoli, Haman; Ghorbanpour, Amir; Razzaghi Asl, Nima

doi:10.30492/ijcce.2021.116590.3821

Unveiling the Full Potential of 2-aryl-1H-phenanthro [9,10-d] imidazoles as Cytotoxic Agents vs AGS, HepG2 and MCF-7 Cell lines

Document Type : Research Article

Authors

¹ Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, I.R. IRAN

² Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, I.R. IRAN

³ Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, I.R. IRAN

⁴ Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, I.R. IRAN

10.30492/ijcce.2021.116590.3821

Abstract

A few 2-aryl-1H-phenanthro [9,10-d] imidazoles were synthesized and assessed for their cytotoxicity against MCF-7, HepG2, and AGS cell lines using MTT assay. Cellular assessments showed that phenanthroimidazoles were extremely potent cytotoxic agents (sub-nanomolar IC₅₀s). Maximum effect was recorded for para-N-phenyl acetamide containing derivative against AGS cells (IC₅₀ 0.07 nM). It was also revealed that phenanthroimidazole derivatives showed better cytotoxicity against MCF-7 and AGS cells when compared to HepG2 cells. Minimum cytotoxicity was reported for para-methylphenyl derivatives within HepG2 cancer cells (IC₅₀ 7608.07 nM). Structure-activity relationship studies indicated that incorporation of nitrogen/oxygen-containing polar groups such as N-acetyl or nitro into para/meta positions of phenyl ring significantly enhanced the cytotoxicity against AGS cells. A similar trend was observed in meta-nitro derivatives vs MCF-7 cells. It was revealed that even the least potent compound exhibited cytotoxic activity in the range of low micromolar IC₅₀. Results of this study proposed 2-aryl-1H-phenanthro [9,10-d] imidazoles as privileged structures for further in vivo studies.

Keywords

Main Subjects

Biochemistry & Biological Chemistry

References

[1] Dueñas-González A., García-López P., Herrera L A., Medina-Franco J.L., González-Fierro A., Candelaria M., The Prince and the Pauper. A Tale of Anticancer Targeted Agents, Molecular Cancer, 7 :82 (2008).

[2] Bray F., Ferlay J., Soerjomataram I., Siegel RL., Torre LA., Jemal A., Global Cancer Statistics: GLOBOCAN, Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA Cancer Journal Clinic, 68(6): 394-424(2018).

[3] Farhood B., Geraily G., Alizadeh A., Incidence and Mortality of Various Cancers in Iran and Compare to other Countries: a Review Article, Iranian Journal of Public Health, 47(3): 309-316 (2018).

[4] Hassan G S., Kadry H H., Abou-Seri S.M., Ali M.M., El-Din Mahmoud A.E., Synthesis and in vitro Cytotoxic Activity of Novel Pyrazolo [3,4-d] Pyrimidines and Related Pyrazole Hydrazones Toward Breast Adenocarcinoma MCF-7 Cell Line, Bioorganic and Medicinal Chemistry, 19: 6808 (2011).

[5] Spaczyńska E., Mrozek-Wilczkiewicz A., Malarz K., Kos J., Gonec T., Oravec M., Gawecki R., Bak A., Dohanosova J., Kapustikova I., Liptaj T., Jampilek J., Musiol R., Design and Synthesis of Anticancer
1-hydroxynaphthalene-2-carboxanilides with a p53 Independent Mechanism of Action, Scientific. Report., 9: 6387(2019).

[6] Bajaj S., Asati V., Singh J., Roy P.P., 1,3,4-Oxadiazoles: An Emerging Scaffold to Target Growth Factors, Enzymes and Kinases as Anticancer Agents, European Journal of Medicinal Chemistry, 97: 124 (2015).

[7] Heidary Alizadeh B., Vosooghi M., Khoobi M., Javidnia A., Panah F., Safavi M., Ardestani S., Shafiee A., Synthesis and Cytotoxic Activity of Novel 9-[hydroxy (substituted phenyl) Methyl]-2,2-dimethyl-2,3,8,9-tetrahydro-4H,10H-Pyrano [2,3-f ]chromene-4,10-diones, Iran. J. Chem. Chem. Eng. (IJCCE), 29: 189 (2010).

[8] Vessally E., Soleimani-Amiri S., Hosseinian A., Edjlalid L ., Bekhradnia A., New Protocols to Access Imidazoles and Their Ring Fused Analogues: Synthesis from N-Propargyl Amines, RSC Advance, 7: 7079 (2017).

[9] Alkahtani H M., Abbas A Y., Wang S., Synthesis and Biological Evaluation of benzo[d]imidazole Derivatives as Potential Anti-Cancer Agents, Bioorganic and Medicinal Chemistry Letters, 22(3): 1317(2012).

[10] Navidpour L., Shadnia H., Shafaroodi H., Amini M., Dehpour A.R., Shafiee A., Design, Synthesis and Biological Evaluation of Substituted 2-Alkylthio-1,5-Diarylimidazoles as Selective COX-2 Inhibitors, Bioorganic and Medicinal Chemistry, 15: 1976 (2007).

[11] Forte B., Malgesini B., Piutti C., Quartieri F., Scolaro A., Papeo G.A., A Submarine Journey: The Pyrrole-Imidazole Alkaloids Drugs, Marine Drugs, 7: 705 (2009).

[12] Bharti A., Pandeya S.N., Various Approaches for Synthesis of Imidazole Derivatives, International journal of research in Ayurveda Pharmacology, 2(4): 1124 (2011).

[13] Özkay Y., Isikdag I., Incesu Z., Akalin G., Synthesis of 2-Substituted-N-[4-(1- methyl-4,5-diphenyl-1H-imidazole-2-yl)phenyl] acetamide derivatives and Evaluation of their Anticancer Activity, European Journal of Medicinal Chemistry, 45: 3320 (2010).

[14] Finlay M.R.V., Acton D.G., Andrews D.M., Barker A.J., Dennis M., Fisher E., Graham M.A., Green C.P., Heaton D W., Karoutchi G., Loddick S A., Morgentin R., Roberts A., Tucker J.A., Weir H.M., Imidazole Piperazines: SAR and Development of a Potent Class of Cyclin-Dependent Kinase Inhibitors with a Novel Binding Mode Bioorg. Bioorganic and Medicinal Chemistry Letters, 18: 4442 (2008).

[15] Li W.T., Hwang D.R., Song J.S., Chen C.P., Chuu J.J., Hu C.B., Lin H.L., Huang C.L., Huang C.Y., Tseng H.Y., Lin C.C., Chen T.W., Lin C.H., Wang H.S., Shen C.C., Chang C.M., Chao Y.S., Chen C.T., Synthesis and Biological Activities of 2-amino-1-arylidenamino Imidazoles as Orally Active Anticancer Agents, Journal of Medicinal Chemistry, 53(6): 2409 (2010).

[16] Sim Y., Kang S., Shin D., Park M., Kay K-Yo., Jongwook P., Synthesis and Properties of New Imidazole Derivatives Including Various Chromophore for OLEDs, Molecular Crystals and Liquid Crystals, 687(1): 27–33 (2019).

[17] Zhiqiang L., Ning X., Yincai X., Chenglong L., Xiaoyue M., Yue W., Fluorine-Substituted Phenanthro [9,10-d]imidazole Derivatives with Optimized Charge-Transfer Characteristics for Efficient Deep-Blue Emitters, Organic Materials, 2:11–19 (2020).

[18] Singh I., Uxami V., Pau K., Synthesis of Naphthalimide-Phenanthro[9,10-d]Imidazole Derivatives: In vitro Evaluation, Binding Interaction with DNA and Topoisomerase Inhibition, Bioorganic Chemistry, 96:103631 (2020).

[19] Shaofeng Y., Shaoqing Z., Biao P., Runda G., Lei W., Imidazole Derivatives for Efficient Organic Light-Emitting Diodes, Journal of Information Display, 21(3): 173-196 (2020).

[20] Mohammadi M.K., Firuzi O., Khoshneviszadeh M., Razzaghi-Asl N., Sepehri S., Miri R., Novel 9-(alkylthio)-Acenaphtho[1,2-e]-1,2,4-triazine Derivatives: Synthesis, Cytotoxic Activity and Molecular Docking Studies on B-cell Lymphoma 2 (Bcl-2), Daru, 22: 2 (2014).

[21] Azizian J., Mohammadi M.K., Firuzi O., Razzaghi-Asl N., Miri R., Synthesis, Biological Activity and Docking Study of Some new Isatin Schiff Base Derivatives, Medicinal Chemistry Research, 21: 3730 (2012).

[22] Razzaghi-Asl N., Miri R., Firuzi O., Assessment of the Cytotoxic Effect of a Series of 1,4-dihydropyridine Derivatives Against Human Cancer Cells, Iranian Journal of Pharmaceutical Research, 15(3): 413 (2016).

[23] Tavakkoli H., Moayedipour T., Fabrication of Perovskite-type Oxide La_0.5Pb_0.5MnO₃Nanoparticles and its Dye Removal Performance, Journal of Nanostructure Chemistry, 4: 116 (2014).

[24] Behmadi H., Roshani M., Saadati S.M., Synthesis of Phenanthrimidazole from 9,10-Phenanthraquinone and Aldehydes by Molecular Iodine as Catalyst, Chinese Chemistry Letters, 20: 5-8 (2009).

[25] Mohammadi Ziarani G., Tavaf E., Fathi Vavsari V., Badiei A., Synthesis of 2,4,5-Trisubstituted Phenanthroimidazole Derivatives using SBA-Pr-SO₃H as a Nanocatalyst, Acta Chimica. Slovenia, 64 701 (2017).

[26] Kidwai M., Mothsra P., Bansal V., Somvanshi R K., Ethayathulla A.S., Dey S., Singh T.P., One-pot Synthesis of Highly Substituted Imidazoles using Molecular Iodine: A Versatile Catalyst, Journal of Molecular Catalyst A: Chemistry, 265: 177-182 (2007).

[27] Samai S., Nandi G.C., Singh P., Singh M S., L-Proline: an Efficient Catalyst for the One-Pot Synthesis of 2, 4, 5-Trisubstituted and 1, 2, 4, 5-Tetrasubstituted Imidazoles, Tetrahedron, 65:10155-10161 (2009).

[28] Karimi A R., Alimohammadi Z., Amini M.M., Wells–Dawson Heteropolyacid Supported on Silica: A Highly Efficient Catalyst for Synthesis of 2, 4, 5-Trisubstituted and 1, 2, 4, 5-Tetrasubstituted Imidazoles, Molecular Diversity, 14: 635-641 (2010).

[29] Janeeka J., Vineet J., An Iodine/DMSO-Catalyzed Sequential One-Pot Approach to 2,4,5-Trisubstituted-1H-Imidazoles from a Methylene Ketones, RSC Advance 8: 37557–37563(2018).

[30] Maleki B., Sedigh Ashrafi S., N-Bromosuccinimide Catalyzed Three-Component One-Pot Efficient Synthesis of 2,4,5-Triaryl-1H-imidazoles from Aldehyde, Ammonium Acetate, and 1,2-Diketone or α-Hydroxyketone, Journal of Mexican Chemical Society, 58: 76-81(2014).

[31] Rostamnia S., Zabardasti A., SBA-15/TFE (SBA-15/2,2,2-Trifluoroethanol) as a Suitable and Effective Metal-free Catalyst for the Preparation of the tri- and tetra-Substituted Imidazoles via One-Pot Multicomponent Method, Journal of Fluorine Chemistry, 144: 69-72 (2012).

[32] Bohlooli S., Jafari N., Jahed S., Cytotoxic Effect of Freeze-dried Extract of Ecballium Elaterium Fruit on Gastric Adenocarcinoma (AGS) and Esophageal Squamous cell Carcinoma (KYSE30) Cell Lines, Journal of Gastrointest Cancer, 43(4): 579 (2012).

[33] Ramanathan P., Synthesis, Spectral Characterization and Biological Studies of 2-(4- Methoxynaphthalen-1-yl)-1-(4-methoxyphenyl)-1H-phenanthro[9,10-D] Imidazole, Modicianl Chemistry Application, 5: 1000242 (2017).

[34] Azarifar D., Asadpoor R., Tavakoli E., Bazouleh M., Sulfonated-Titanomagnetite Nanoparticles as Potential and Recyclable Catalyst for the Synthesis of Dihydroquinazoline and Hexahydroquinoline Derivatives under Solvent-Free Condition, Iran. J. Chem. Chem. Eng. (IJCCE), 40(2): 367-381(2021).