Anticancer Effects of Novel Tetrahydro-Dimethyl-Xanthene-Diones

Author(s): Alagumuthu Manikandan, Arumugam Sivakumar, Poonam S. Nigam, Ayyakannu A. Napoleon*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 7 , 2020

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Graphical Abstract:


Abstract:

Background: The derivatives of xanthene are known to have promising anticancer properties, in comparison to xanthene itself.

Objective: The object of our study was to develop few xanthene derivatives (a family of fifteen novel 3,4,6,7- tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H, 9H)-diones encoded as 4a-4m), which were effectively prepared through regioselective synthesis approach, and to test their anticancer effects.

Methods: A series of cell lines were used in this study, first to assess the cytotoxicity and then the drug efficacy of target compounds, consecutively. Prior to MTT assay, the compounds were analysed for their antioxidant properties, since oxidative stress is an important factor in the development of many cancer types. The anticancer properties of 4a-m have been assessed over in silico (molecular docking and ADMET assessments) and in vitro (MTT assay) methods.

Results: Compounds 4h and 4i showed a relative percentage anticancer activity of 86.25±1.25 & 89.74±1.64 against BT474 (ER+HER2+), and 90.56±1.18 & 93.24±1.80 against MCF-7 (ER-HER2), respectively.

Conclusion: The animal model and pre-clinical studies for 4h and 4i should be performed in order to develop them as future anticancer agents.

Keywords: Anticancer, antioxidant, cytotoxicity, molecular docking, MTT assay, xanthene-diones.

[1]
Kadirappa, A.; Manikandan, A.; Reddy, S.M.; Napoleon, A.A. Copper-catalyzed quinoline derivatives evaluated as a new class of anticancer agents: Design, synthesis and molecular validations. J. Heterocycl. Chem., 2018, 55, 1669-1677.
[2]
Alagumuthu, M.; Arumugam, S. Molecular explorations of substituted 2-(4-phenylquinolin-2-yl) phenols as phosphoinositide 3-kinase inhibitors and anticancer agents. Cancer Chemother. Pharmacol., 2017, 79(2), 389-397.
[http://dx.doi.org/10.1007/s00280-016-3227-z] [PMID: 28054203]
[3]
Rajesh Kumar, M.; Alagumuthu, M.; Violet Dhayabaran, V. N-substituted hydroxynaphthalene imino-oxindole derivatives as new class of PI3-kinase inhibitor and breast cancer drug: Molecular validation and structure-activity relationship studies. Chem. Biol. Drug Des., 2018, 91(1), 277-284.
[http://dx.doi.org/10.1111/cbdd.13079] [PMID: 28791774]
[4]
Subramamiam, P.; Ramasubbu, C.; Athiramu, S.; Arumugam, S.; Alagumuthu, M. Pharmacological explorations of eco-friendly amide substituted (Z)-β-enaminones as anti-breast cancer drugs. Arch. Pharm. (Weinheim), 2019, 352(1), e1800244
[PMID: 30515835]
[5]
Muralidharan, V.P.; Alagumuthu, M.; Iyer, S.K. Iodine catalyzed three component synthesis of 1-((2-hydroxy naphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives: Rationale as potent PI3K inhibitors and anticancer agents. Bioorg. Med. Chem. Lett., 2017, 27(11), 2510-2514.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.093] [PMID: 28462836]
[6]
Vivek, P.M.; Manikandan, A.; Arumugam, S.; Iyer, S.K. Molecular substantiation and drug efficacy of relatively high molecular weight SJ BINOLs; appraised as breast cancer medication and PI3Kinase inhibitors. J. Heterocycl. Chem., 2018, 55(6), 1339-1345.
[http://dx.doi.org/10.1002/jhet.3166]
[7]
Marat, A.L.; Haucke, V. Phosphatidylinositol 3-phosphates-at the interface between cell signalling and membrane traffic. EMBO J., 2016, 35(6), 561-579.
[http://dx.doi.org/10.15252/embj.201593564] [PMID: 26888746]
[8]
Bleeker, F.E.; Lamba, S.; Zanon, C.; Molenaar, R.J.; Hulsebos, T.J.; Troost, D.; van Tilborg, A.A.; Vandertop, W.P.; Leenstra, S.; van Noorden, C.J.; Bardelli, A. Mutational profiling of kinases in glioblastoma. BMC Cancer, 2014, 14, 718.
[http://dx.doi.org/10.1186/1471-2407-14-718] [PMID: 25256166]
[9]
Kaya, M.; Demir, E.; Bekci, H. Synthesis, characterization and antimicrobial activity of novel xanthene sulfonamide and carboxamide derivatives. J. Enzyme Inhib. Med. Chem., 2013, 28(5), 885-893.
[http://dx.doi.org/10.3109/14756366.2012.692087] [PMID: 22803669]
[10]
Shubha, J.; Neelaiah, B.; Srinivasa, R.J.; Harshada, S.; Surya, P.D. Synthesis, antitubercular and antifungal activities of heteroaryl-substituted oxiranes derived from Baylis–Hillman adducts. Med. Chem. Res., 2012, 21, 2744-2748.
[http://dx.doi.org/10.1007/s00044-011-9802-2]
[11]
Joo, R.K.; Stephen, M. Synthesis of antifungal agents from Xanthenes and thiazine dyes and analysis of their effect. Nanomaterials (Basel), 2016, 6(12), 243.
[http://dx.doi.org/10.3390/nano6120243]
[12]
Partha, S.B.; Aparoop, D.; Nainwal, L.M.; Mohanta, T.K.; Kumawat, M.K.; Mohapatra, P.K.; Parida, P. Design, synthesis, and antidiabetic activity evaluation of some novel xanthones derivatives targeting α-glucosidase. Bangladesh J. Pharmacol., 2016, 11, 308-318.
[http://dx.doi.org/10.3329/bjp.v11i2.25851]
[13]
Dinesh, K.; Pooja, S.; Harmanpreet, S.; Kunal, N.; Girish, K.G.; Subheet, K.J.; Fidele, N.K. The value of pyrans as anticancer scaffolds in medicinal chemistry. RSC Advances, 2017, 7, 36977-36999.
[http://dx.doi.org/10.1039/C7RA05441F]
[14]
Giri, R.; Goodell, J.R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D.M. Synthesis and cancer cell cytotoxicity of substituted xanthenes. Bioorg. Med. Chem., 2010, 18(4), 1456-1463.
[http://dx.doi.org/10.1016/j.bmc.2010.01.018] [PMID: 20129790]
[15]
Kostakis, I.K.; Magiatis, P.; Pouli, N.; Marakos, P.; Skaltsounis, A.L.; Pratsinis, H.; Léonce, S.; Pierré, A. Design, synthesis, and antiproliferative activity of some new pyrazole-fused amino derivatives of the pyranoxanthenone, pyranothioxanthenone, and pyranoacridone ring systems: a new class of cytotoxic agents. J. Med. Chem., 2002, 45(12), 2599-2609.
[http://dx.doi.org/10.1021/jm011117g] [PMID: 12036369]
[16]
Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med., 2010, 49(11), 1603-1616.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.006] [PMID: 20840865]
[17]
Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; LLeonart, M.E. Oxidative stress and cancer: an overview. Ageing Res. Rev., 2013, 12(1), 376-390.
[http://dx.doi.org/10.1016/j.arr.2012.10.004] [PMID: 23123177]
[18]
Napoleon, A.A.; Nawaz Khan, F.R.; Jeong, E.D.; Chung, E.H. Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid-catalyzed three-component domino reaction. Tetrahedron Lett., 2014, 55, 5656-5659.
[http://dx.doi.org/10.1016/j.tetlet.2014.08.040]
[19]
Manikandan,, A.;; Muralidharan, V.P.; Andrew, M.; Ahmed, M.H.; Iyer, S.K.; Arumugam, S. Computational approaches to develop isoquinoline based antibiotics through DNA gyrase inhibition mechanisms unveiled through antibacterial evaluation and molecular docking. Mol. Inform., 2018, 37, 1800048
[http://dx.doi.org/10.1002/minf.201800048]
[20]
Manikandan, A.; Moharil, P.; Sathishkumar, M.; Muñoz-Garay, C.; Sivakumar, A. Therapeutic investigations of novel indoxyl-based indolines: A drug target validation and Structure-Activity Relationship of angiotensin-converting enzyme inhibitors with cardiovascular regulation and thrombolytic potential. Eur. J. Med. Chem., 2017, 141, 417-426.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.076] [PMID: 29032034]
[21]
Alagumuthu, M.; Arumugam, S. Molecular docking, discovery, synthesis, and pharmacological properties of new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents. Bioorg. Med. Chem., 2017, 25(4), 1448-1455.
[http://dx.doi.org/10.1016/j.bmc.2017.01.007] [PMID: 28094220]
[22]
Manikandan, A.; Ravichandran, S.; Kumaravel, K.; Sivakumar, A.; Rethna, P. Molecular docking and in vitro evaluations of Hippocampus trimaculatus (seahorse) extracts as anti-inflammatory compounds. Int. J. Bioinform. Res. Appl., 2016, 12(4), 355-371.
[http://dx.doi.org/10.1504/IJBRA.2016.080722]
[23]
Thangarasu, P.; Thamarai Selvi, S.; Manikandan, A. Unveiling novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl)quinolines as GPCR ligands via PI3-kinase/PAR-1 antagonism and platelet aggregation valuations; development of a new class of anticancer drugs with thrombolytic effects. Bioorg. Chem., 2018, 81, 468-480.
[http://dx.doi.org/10.1016/j.bioorg.2018.09.011] [PMID: 30243238]
[24]
Kumar, M.R.; Manikandan, A.; Sivakumar, A.; Dhayabaran, V.V. An eco-friendly catalytic system for multicomponent, one-pot synthesis of novel spiro-chromeno indoline-triones and their anti-prostate cancer potentials evaluated via alkaline phosphatase inhibition mechanism. Bioorg. Chem., 2018, 81, 44-54.
[http://dx.doi.org/10.1016/j.bioorg.2018.07.037] [PMID: 30118985]
[25]
Manikandan, A.; Nemani, S.C.; Sadheeshkumar, V.; Arumugam, S. Spectroscopic investigations for photostability of Diclofenac sodium complexed with hydroxypropyl-β-cyclodextrin. J. App.Pharm. Sci.,, 2016, 6(04), 098-103.
[http://dx.doi.org/10.7324/JAPS.2016.60414]
[26]
Lee, H.C.; Wei, Y.H. Mitochondrial alterations, cellular response to oxidative stress and defective degradation of proteins in aging. Biogerontology, 2001, 2(4), 231-244.
[http://dx.doi.org/10.1023/A:1013270512172] [PMID: 11868898]


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Article Details

VOLUME: 20
ISSUE: 7
Year: 2020
Page: [909 - 916]
Pages: 8
DOI: 10.2174/1871520620666200318094138
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