Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In silico and In vitro Determination of Antiproliferative Activity of Series N-Pyrrolyl Hydrazide-Hydrazones and Evaluation of their Effects on Isolated Rat Mycrosomes and Hepatocytes

Author(s): Maya Georgieva*, Diana Tzankova, Emilio Mateev, Borislav Angelov, Magdalena Kondeva-Burdina, Georgi Momekov, Virginia Tzankova and Alexander Zlatkov

Volume 23, Issue 3, 2023

Published on: 26 August, 2022

Page: [346 - 359] Pages: 14

DOI: 10.2174/1871520622666220701114306

Price: $65

conference banner
Abstract

Background: The significant increase in patients suffering from different types of cancer, guides scientists to take prompt measures in the development of novel and effective antiproliferative agents, where the intercalation of heterocyclic fragments in the designed molecules has proven to be a useful practice.

Objective: The newly synthesized compounds were obtained from the corresponding 1,4-dicarbonyl derivative through multicomponent reactions to produce biologically active target molecules and assessed by in silico and in vitro assays for their possible antitumor activity.

Methods: The pharmacological bioassay was conducted in the panel of human tumor cell lines (i) SKW-3 (ACC 53) – human T-cell leukemia and (ii) HL-60 (ACC 3) - human acute myeloid leukemia (AML). The statistical processing of MTT data included the paired Student’s t-test with p ≤ 0.05 set as significance level.

Results: All evaluated structures displayed a higher cytotoxic effect against the acute myeloid leukemia HL-60 with 11o and 11p as the most active compared to the activity against SKW-3 cell line. Throughout the cytotoxicity screening two molecules, 11l and 12o, displayed comparable chemosensitivity on both cell lines. The corresponding hepatotoxicity on isolated rat hepatocytes and microsomes was also established, identifying 11, 12 and 12a as the least toxic and 11x, 11d, 12x and 12d as the most toxic derivatives.

Conclusion: As the most promising compound is underlined ethyl 1-(2-(2-((1-acetyl-1H-indol-3-yl)methylene)hydrazinyl)-2- oxoethyl)-5-(4-bromophenyl)-2-methyl-1H-pyrrole-3-carboxylate (11l) demonstrating highest activity on both evaluated tumor cell lines, decreased hepatotoxicity on all evaluated parameters and docking score of -7.517 kcal/mol.

Keywords: antiproliferative activity, N-pyrrolyl hydrazide-hydrazones, cytotoxicity, isolated rat microsomes and hepatocytes

« Previous Next »
Graphical Abstract

[1]
Ferlay, J.; Ervik, M.; Lam, F.; Colombet, M.; Mery, L.; Piñeros, M. Global Cancer Observatory: Cancer Today; International Agency for Research on Cancer: Lyon, 2020. Available from: https://gco.iarc.fr/today
[2]
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.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[4]
Vaijayanthi, T.; Bando, T.; Pandian, G.N.; Sugiyama, H. Progress and prospects of pyrrole-imidazole polyamide-fluorophore conjugates as sequence-selective DNA probes. ChemBioChem, 2012, 13(15), 2170-2185.
[http://dx.doi.org/10.1002/cbic.201200451] [PMID: 23023993]
[5]
Bianco, M.D.C.A.D.; Marinho, D.I.L.F.; Hoelz, L.V.B.; Bastos, M.M.; Boechat, N. Pyrroles as privileged scaffolds in the search for new potential HIV inhibitors. Pharmaceuticals (Basel), 2021, 14(9), 893-910.
[http://dx.doi.org/10.3390/ph14090893] [PMID: 34577593]
[6]
Li, I.T.S.; Ha, T.; Chemla, Y.R. Mapping cell surface adhesion by rotation tracking and adhesion footprinting. Sci. Rep., 2017, 7(44502), 44502.
[http://dx.doi.org/10.1038/srep44502] [PMID: 28290531]
[7]
Garner, R.M.; Skariah, G.; Hadjitheodorou, A.; Belliveau, N.M.; Savinov, A.; Footer, M.J.; Theriot, J.A. Neutrophil-like HL-60 cells expressing only GFP-tagged β-actin exhibit nearly normal motility. Cytoskeleton (Hoboken), 2020, 77(5-6), 181-196.
[http://dx.doi.org/10.1002/cm.21603] [PMID: 32072765]
[8]
Hee-Don, C.; Ritika, D.; Bruce, T.; Kara, L.D.; Norman, J.L.; Kathleen, M.S. RSK inhibition induces metaphase arrest and apoptosis in acute myeloid leukemia cells. Blood, 2017, 130(Suppl. 1), 2530.
[9]
Padrón, J.M.; Tejedor, D.; Santos-Expósito, A.; García-Tellado, F.; Martín, V.S.; Villar, J. Antiproliferative activity in HL60 cells by tetrasubstituted pyrroles: A structure-activity relationship study. Bioorg. Med. Chem. Lett., 2005, 15(10), 2487-2490.
[http://dx.doi.org/10.1016/j.bmcl.2005.03.069] [PMID: 15863302]
[10]
Dowell, B.L.; Gore, I., Jr; McCormick, G.M.; Haynes, B.F.; Metzgar, R.S. A monoclonal antibody reactive with a second epitope of the 67,000-dalton human T cell antigen. Hum. Immunol., 1983, 7(2), 95-104.
[http://dx.doi.org/10.1016/S0198-8859(83)80010-X] [PMID: 6190792]
[11]
Konstantinov, S.M.; Kostovski, A.; Topashka-Ancheva, M.; Genova, M.; Berger, M.R. Cytotoxic efficacy of bendamustine in human leukemia and breast cancer cell lines. J. Cancer Res. Clin. Oncol., 2002, 128(5), 271-278.
[http://dx.doi.org/10.1007/s00432-002-0331-8] [PMID: 12029443]
[12]
Al-Qathama, A.; Gibbons, S.; Prieto, J.M. Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375. Oncotarget, 2017, 8(56), 95999-96012.
[http://dx.doi.org/10.18632/oncotarget.21625] [PMID: 29221182]
[13]
Georgieva, M.; Kondeva-Burdina, M.; Mitkov, J.; Tzankova, V.; Momekov, G.; Zlatkov, A. Determination of the antiproliferative activity of new theobromine derivatives and evaluation of their in vitro hepatotoxic effects. Anticancer. Agents Med. Chem., 2016, 16(7), 925-932.
[http://dx.doi.org/10.2174/1871520616666151116122633] [PMID: 26567622]
[14]
Chen, Yu.; Pohlhaus, D.T. In silico docking and scoring of fragments. Drug Discov. Today. Technol., 2010, 7(3), e147-e202.
[http://dx.doi.org/10.1016/j.ddtec.2010.11.002] [PMID: 24103766]
[15]
Jongejan, A.; de Graaf, C.; Vermeulen, N.P.; Leurs, R.; de Esch, I.J. The role and application of in silico docking in chemical genomics research. Methods Mol. Biol., 2005, 310, 63-91.
[http://dx.doi.org/10.1007/978-1-59259-948-6_5] [PMID: 16350947]
[16]
Yadav, M.; Dhagat, S.; Eswari, J.S. Structure based drug design and molecular docking studies of anticancer molecules paclitaxel, etoposide and topotecan using novel ligands. Curr. Drug Discov. Technol., 2020, 17(2), 183-190.
[http://dx.doi.org/10.2174/1570163816666190307102033] [PMID: 30848204]
[17]
Bijev, A.; Georgieva, M. Pyrrole-based hydrazones synthesized and evaluated in vitro as potential tuberculostatics. Lett. Drug Des. Discov., 2010, 7(6), 430-437.
[http://dx.doi.org/10.2174/157018010791306588]
[18]
Georgieva, M.; Bijev, A.; Prodanova, P. Synthesis and comparative study of tuberculostatic activity of pyrrole-based hydrazones related to structural variations. Pharmacia, 2010, LVII(1-4), 3-14.
[19]
Release, S. 2021-3: LigPrep; Glide Protein Data Bank Schrödinger, LLC: New York, NY, 2021.
[20]
Available from: https://www.rcsb.org
[21]
Mechchate, H.; Costa de Oliveira, R.; Es-Safi, I.; Vasconcelos Mourão, E.M.; Bouhrim, M.; Kyrylchuk, A.; Soares Pontes, G.; Bousta, D.; Grafov, A. Antileukemic activity and molecular docking study of a polyphenolic extract from coriander seeds. Pharmaceuticals (Basel), 2021, 14(8), 770-786.
[http://dx.doi.org/10.3390/ph14080770] [PMID: 34451867]
[22]
Greenwood, J.R.; Calkins, D.; Sullivan, A.P.; Shelley, J.C. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J. Comput. Aided Mol. Des., 2010, 24(6-7), 591-604.
[http://dx.doi.org/10.1007/s10822-010-9349-1] [PMID: 20354892]
[23]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[24]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[25]
Freshney, R.I. Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th ed; Wiley & Sons: New York, 2011.
[26]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[27]
Konstantinov, S.M.; Eibl, H.; Berger, M.R. BCR-ABL influences the antileukaemic efficacy of alkylphosphocholines. Br. J. Haematol., 1999, 107(2), 365-380.
[http://dx.doi.org/10.1046/j.1365-2141.1999.01700.x] [PMID: 10583226]
[28]
Simeonova, R.; Vitcheva, V.; Kondeva-Burdina, M.; Krasteva, I.; Manov, V.; Mitcheva, M. Hepatoprotective and antioxidant effects of saponarin, isolated from Gypsophila trichotoma Wend. on paracetamol-induced liver damage in rats. BioMed Res. Int., 2013, 2013, 757126.
[http://dx.doi.org/10.1155/2013/757126] [PMID: 23878818]
[29]
Concil of Europe, European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS123). 1991. Available from: http://conventions.coe.int/treaty/en/treaties/html/123.htm (Accessed December 30, 2014).
[30]
Gevrenova, R.; Kondeva-Burdina, M.; Denkov, N.; Zheleva-Dimitrova, D. Flavonoid profiles of three Bupleurum species and in vitro hepatoprotective of activity Bupleurum flavum Forsk. Pharmacogn. Mag., 2015, 11(41), 14-23.
[http://dx.doi.org/10.4103/0973-1296.149680] [PMID: 25709205]
[31]
Guengerich, F.P. Analysis and characterizaton of enzymes.Principles and methods of toxicology; Hayes, A.W., Ed.; Raven Press: New York, 1989, pp. 777-814.
[32]
Deby, C.; Goutier, R. New perspectives on the biochemistry of superoxide anion and the efficiency of SOD. Biochem. Pharmacol., 1990, 39, 399-405.
[http://dx.doi.org/10.1016/0006-2952(90)90043-K] [PMID: 2154984]
[33]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 1951, 193(1), 265-275.
[http://dx.doi.org/10.1016/S0021-9258(19)52451-6] [PMID: 14907713]
[34]
Mitcheva, M.; Kondeva, M.; Vitcheva, V.; Nedialkov, P.; Kitanov, G. Effect of benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity in freshly isolated rat hepatocytes. Redox Rep., 2006, 11(1), 3-8.
[http://dx.doi.org/10.1179/135100006X100968] [PMID: 16571270]
[35]
Bergmeyer, H.U.; Gawehn, K.; Grassl, M. Methods of Enzymatic Analysis; Verlag Chemie: Weinheim, 1974, pp. 481-482.
[36]
Fau, D.; Berson, A.; Eugene, D.; Fromenty, B.; Fisch, C.; Pessayre, D. Mechanism for the hepatotoxicity of the antiandrogen, nilutamide. Evidence suggesting that redox cycling of this nitroaromatic drug leads to oxidative stress in isolated hepatocytes. J. Pharmacol. Exp. Ther., 1992, 263(1), 69-77.
[PMID: 1403804]
[37]
Chandrashekhar, R.; Ram, B.; Bhavani, N.L.; Bakshi, V. Molecular docking studies of hydrazide-hydrazone derivatives of gossypol against bcl-2 family anti-apoptotic targets. Drug Des., 2017, 6, 155.
[38]
Sharma, P.; Pollyea, D.A. Shutting down acute myeloid leukemia and myelodysplastic syndrome with BCL-2 family protein inhibition. Curr. Hematol. Malig. Rep., 2018, 13(4), 256-264.
[http://dx.doi.org/10.1007/s11899-018-0464-8] [PMID: 29982865]
[39]
Wei, Y.; Cao, Y.; Sun, R.; Cheng, L.; Xiong, X.; Jin, X.; He, X.; Lu, W.; Zhao, M. Targeting Bcl-2 proteins in acute myeloid leukemia. Front. Oncol., 2020, 10(584974), 1-11.
[http://dx.doi.org/10.3389/fonc.2020.584974]
[40]
Gokhale, P.; Chauhan, A.P.S.; Arora, A.; Khandekar, N.; Nayarisseri, A.; Singh, S.K. FLT3 inhibitor design using molecular docking based virtual screening for acute myeloid leukemia. Bioinformation, 2019, 15(2), 104-115.
[http://dx.doi.org/10.6026/97320630015104] [PMID: 31435156]
[41]
Li Petri, G.; Spanò, V.; Spatola, R.; Holl, R.; Raimondi, M.V.; Barraja, P.; Montalbano, A. Bioactive pyrrole-based compounds with target selectivity. Eur. J. Med. Chem., 2020, 208(112783), 112783.
[http://dx.doi.org/10.1016/j.ejmech.2020.112783] [PMID: 32916311]
[42]
Timson, J. The effect of caffeine on the mitosis of human lymphocytes in culture. Br. J. Pharmacol., 1970, 38(4), 731-734.
[http://dx.doi.org/10.1111/j.1476-5381.1970.tb09881.x] [PMID: 5445691]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy