Generic placeholder image

Letters in Drug Design & Discovery

Author(s): Hamidreza Akrami, Bibi Fatemeh Mirjalili, Omidreza Firuzi, Azadeh Hekmat, Ali Akbar Saboury, Ramin Miri, Omid Sabzevari, Morteza Pirali-Hamedani, Fereshteh Jeivad, Setareh Moghimi, Saeed Emami, Alireza Foroumadi* and Mehdi Khoobi*

DOI: 10.2174/1570180816666190712102119

DownloadDownload PDF Flyer Cite As
Cytotoxic Activity and DNA Binding Property of New Aminopyrimidine Derivatives

Page: [640 - 654] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: Chromene and anilinopyrimidine heterocyclics are attractive anticancer compounds that have inspired many researchers to design novel derivatives bearing improved anticancer activity.

Methods: A series of pyrimidine-fused benzo[f]chromene derivatives 6a-x were synthesized as anticancer hybrids of 1H-benzo[f]chromenes and anilinopyrimidines. The inhibitory activity of the synthesized compounds 6a-x against cell viability of human chronic myelogenous leukemia (K562), human acute lymphoblastic leukemia (MOLT-4) and human breast adenocarcinoma (MCF-7) cell lines was evaluated using MTT assay. The interaction of the most promising compound with calf-thymus DNA was also studied using spectrometric titrations and Circular Dichroism (CD) spectroscopy.

Results: Most compounds showed promising activity against tested cell lines. Among them, 2,4- dimethoxyanilino derivative 6g exhibited the best profile of activity against tested cell lines (IC50s = 1.6-6.1 μM) with no toxicity against NIH3T3 normal cell (IC50 >200 μM). The spectrometric studies exhibited that compound 6g binds to DNA strongly and may change DNA conformation significantly, presumably via a groove binding mechanism.

Conclusion: The results of this study suggest that the prototype compound 6g can be considered as a novel lead compound for the design and discovery of novel anticancer agents.

Keywords: Anti-cancer activity, benzo[f]chromene, polycyclic compounds, multi-component reactions, DNA-binding, aminopyrimidine derivatives.

Graphical Abstract

[1]
Senapati, S.; Mahanta, A.K.; Kumar, S.; Maiti, P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct. Target. Ther., 2018, 3, 7-12.
[http://dx.doi.org/10.1038/s41392-017-0004-3] [PMID: 29560283]
[2]
Stankovic, T.; Dinic, J.; Podolski-Renic, A.; Musso, L.; Buric, S.S.; Dallavalle, S.; Pesic, M. Dual inhibitors as a new challenge for cancer multidrug resistance treatment. Curr. Med. Chem., 2019, 26(33), 6074-6106.
[http://dx.doi.org/10.2174/0929867325666180607094856] [PMID: 29874992]
[3]
Magalhaes, L.G.; Ferreira, L.L.G.; Andricopulo, A.D. Recent advances and perspectives in cancer drug design, An Acad. An. Acad. Bras. Cienc., 2018, 90(1)(Suppl. 2), 1233-1250.
[http://dx.doi.org/10.1590/0001-3765201820170823] [PMID: 29768576]
[4]
Khoobi, M.; Foroumadi, A.; Emami, S.; Safavi, M.; Dehghan, G.; Alizadeh, B.H.; Ramazani, A.; Ardestani, S.K.; Shafiee, A. Coumarin-based bioactive compounds: acile synthesis and biological evaluation of coumarin-fused 1,4-thiazepines. Chem. Biol. Drug Des., 2011, 78(4), 580-586.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01175.x] [PMID: 21740531]
[5]
Ramazani, A.; Khoobi, M.; Torkaman, A.; Nasrabadi, F.Z.; Forootanfar, H.; Shakibaie, M.; Jafari, M.; Ameri, A.; Emami, S.; Faramarzi, M.A.; Foroumadi, A.; Shafiee, A. One-pot, four-component synthesis of novel cytotoxic agents 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-(1H-pyrrol-2-yl)methanamines. Eur. J. Med. Chem., 2014, 78, 151-156.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.049] [PMID: 24681979]
[6]
Firoozpour, L.; Edraki, N.; Nakhjiri, M.; Emami, S.; Safavi, M.; Ardestani, S.K.; Khoshneviszadeh, M.; Shafiee, A.; Foroumadi, A. Cytotoxic activity evaluation and QSAR study of chromene-based chalcones. Arch. Pharm. Res., 2012, 35(12), 2117-2125.
[http://dx.doi.org/10.1007/s12272-012-1208-2] [PMID: 23263805]
[7]
Azizmohammadi, M.; Khoobi, M.; Ramazani, A.; Emami, S.; Zarrin, A.; Firuzi, O.; Miri, R.; Shafiee, A. 2H-chromene derivatives bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential anticancer agents. Eur. J. Med. Chem., 2013, 59, 15-22.
[http://dx.doi.org/10.1016/j.ejmech.2012.10.044] [PMID: 23202485]
[8]
Molaverdi, F.; Khoobi, M.; Emami, S.; Alipour, M.; Firuzi, O.; Foroumadi, A.; Dehghan, G.; Miri, R.; Shaki, F.; Jafarpour, F.; Shafiee, A. Polyoxygenated cinnamoylcoumarins as conformationally constrained analogs of cytotoxic diarylpentanoids: Synthesis and biological activity. Eur. J. Med. Chem., 2013, 68, 103-110.
[http://dx.doi.org/10.1016/j.ejmech.2013.07.014] [PMID: 23973822]
[9]
Elinson, M.N.; Ilovaisky, A.I.; Merkulova, V.M.; Belyakov, P.A.; Chizhov, A.O.; Nikishin, G.I. Solvent-free cascade reaction: direct multicomponent assembling of 2-amino-4H-chromene scaffold from salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes. Tetrahedron, 2010, 66, 4043-4048.
[http://dx.doi.org/10.1016/j.tet.2010.04.024]
[10]
Rao, M.S.; Chhikara, B.S.; Tiwari, R.; Shirazi, A.N.; Parang, K.; Kumar, A. A greener synthesis of 2-aminochromenes in ionic liquid and evaluation of their antiproliferative activities. J. Chem. Biol. Interface, 2012, 2, 362-372.
[11]
Mohamed, H.M.; Fouda, A.M.; Khattab, E.S.A.E.H.; Agrody, A.M.E.; Afifi, T.H. Synthesis, in-vitro cytotoxicity of 1H-benzo[f]chromene derivatives and structure-activity relationships of the 1-aryl group and 9-position. Z. Natforsch. C J. Biosci., 2017, 72(5-6), 161-171.
[http://dx.doi.org/10.1515/znc-2016-0139] [PMID: 27831925]
[12]
Gorle, S.; Maddila, S.; Maddila, S.N.; Naicker, K.; Singh, M.; Singh, P.; Jonnalagadda, S.B. Synthesis, molecular docking study and in vitro anticancer activity of tetrazole linked benzochromene derivatives. Anticancer. Agents Med. Chem., 2017, 17(3), 464-470.
[http://dx.doi.org/10.2174/1871520616666160627090249] [PMID: 27357544]
[13]
Hu, X.; Wang, D.; Tong, Y.; Tong, L.; Wang, X.; Zhu, L.; Xie, H.; Li, S.; Yang, Y.; Xu, Y. Design, synthesis, and evaluation of ribose-modified anilinopyrimidine derivatives as EGFR tyrosine kinase inhibitors. Front Chem., 2017, 5, 101.
[http://dx.doi.org/10.3389/fchem.2017.00101] [PMID: 29250520]
[14]
Gandin, V.; Ferrarese, A.; Dalla Via, M.; Marzano, C.; Chilin, A.; Marzaro, G. Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily. Sci. Rep., 2015, 5, 16750.
[http://dx.doi.org/10.1038/srep16750] [PMID: 26568452]
[15]
Zhang, Q.; Liu, Y.; Gao, F.; Ding, Q.; Cho, C.; Hur, W.; Jin, Y.; Uno, T.; Joazeiro, C.A.; Gray, N. Discovery of EGFR selective 4,6-disubstituted pyrimidines from a combinatorial kinase-directed heterocycle library. J. Am. Chem. Soc., 2006, 128(7), 2182-2183.
[http://dx.doi.org/10.1021/ja0567485] [PMID: 16478150]
[16]
Akrami, H.; Safavi, M.; Mirjalili, B.F.; Dehghani Ashkezari, M.; Dadfar, F.; Mohaghegh, N.; Emami, S.; Salehi, F.; Nadri, H.; Ardestani, S.K.; Firoozpour, L.; Khoobi, M.; Foroumadi, A. Facile synthesis and antiproliferative activity of 7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amines. Eur. J. Med. Chem., 2017, 127, 128-136.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.037] [PMID: 28039771]
[17]
Chakera, A.; Zribi, F.; Nepveub, F.; Chabchoub, F. Microwave irradiation: Novel and facile methods for the synthesis of new pyrimidinones. Chin. Chem. Lett., 2014, 25, 1207-1210.
[http://dx.doi.org/10.1016/j.cclet.2014.03.048]
[18]
Kumar, A.; Sharma, S.; Maurya, R.A.; Sarkar, J. Diversity oriented synthesis of benzoxanthene and benzochromene libraries via one-pot, three-component reactions and their anti-proliferative activity. J. Comb. Chem., 2010, 12(1), 20-24.
[http://dx.doi.org/10.1021/cc900143h] [PMID: 19954208]
[19]
Moosavi-Zare, A.R.; Zolfigol, M.A.; Khaledian, O.; Khakyzadeh, V. Darestani farahani, M.; Beyzavi, M.H.; Kruger, H.G. Tandem Knoevenagel-Michael-cyclocondensation reaction of malononitrile, various aldehydes and 2-naphthol over acetic acid functionalized ionic liquid. Chem. Eng. J., 2014, 248, 122-127.
[http://dx.doi.org/10.1016/j.cej.2014.03.035]
[20]
Yarahmadi, H.; Shaterian, H.R. Basic magnetic nanoparticles as efficient catalysts for the preparation of naphthopyrane derivatives. J. Chem. Res., 2012, 36, 49-51.
[http://dx.doi.org/10.3184/174751912X13264750348839]
[21]
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]
[22]
Hekmat, A.; Saboury, A.A.; Divsalar, A. The effects of silver nanoparticles and doxorubicin combination on DNA structure and its antiproliferative effect against T47D and MCF7 cell lines. J. Biomed. Nanotechnol., 2012, 8(6), 968-982.
[http://dx.doi.org/10.1166/jbn.2012.1451] [PMID: 23030005]
[23]
Sankappa Rai, U.; Isloor, A.M. shetty, P.; Vijesh, A.M.; Prabhu, N.; Isloor, S.; Thiageeswaran, M.; Fun, H.K. Novel chromeno [2,3-b]-pyrimidine derivatives as potential anti-microbial agents. Eur. J. Med. Chem., 2010, 45(6), 2695-2699.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.040] [PMID: 20231044]
[24]
Wang, J.; Wu, J.; Zhang, Z.; Zhang, X.; Pan, Z.; Wang, L.; Xu, L.; Li, H.; Tong, J. Sonocatalytic damage of bovine serum albumin (BSA) in the presence of nanometer anatase titanium dioxide (TiO2). Ultrasound Med. Biol., 2006, 32(1), 147-152.
[http://dx.doi.org/10.1016/j.ultrasmedbio.2005.09.016] [PMID: 16364806]
[25]
Pashah, Z.; Hekmat, A.; Hesami Tackallou, S. Structural effects of Diamond nanoparticles and Paclitaxel combination on calf thymus DNA. Nucleosides Nucleotides Nucleic Acids, 2019, 38(4), 249-278.
[http://dx.doi.org/10.1080/15257770.2018.1515440] [PMID: 30922151]
[26]
Hekmat, A.; Saboury, A.A.; Divsalar, A.; Seyedarabi, A. Structural effects of TiO2 nanoparticles and doxorubicin on DNA and their antiproliferative roles in T47D and MCF7 cells. Anticancer. Agents Med. Chem., 2013, 13(6), 932-951.
[http://dx.doi.org/10.2174/18715206113139990142] [PMID: 23387974]
[27]
Pasternack, R.F.; Caccam, M.; Keogh, B.; Stephenson, T.A.; Williams, A.P.; Gibbs, E.J. Long-range fluorescence quenching of ethidium ion by cationic porphyrins in the presence of DNA. J. Am. Chem. Soc., 1991, 113, 6835-6840.
[http://dx.doi.org/10.1021/ja00018a019]
[28]
Wang, H.; Zhang, M.; Lv, Q.; Yue, N.; Gong, B. Determination of berberine and the study of fluorescence quenching mechanism between berberine and enzyme-catalyzed product. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2009, 73(4), 682-686.
[http://dx.doi.org/10.1016/j.saa.2009.03.017] [PMID: 19380247]
[29]
Meadows, K.A.; Liu, F.; Sou, J.; Hudson, B.P.; McMillin, D.R. Spectroscopic and photophysical studies of the binding interactions between copper phenanthroline complexes and RNA. Inorg. Chem., 1993, 32, 2919-2923.
[http://dx.doi.org/10.1021/ic00065a020]
[30]
Tan, M.; Zhu, J.; Pan, Y.; Chen, Z.; Liang, H.; Liu, H.; Wang, H. Synthesis, cytotoxic activity, and DNA binding properties of copper (II) complexes with hesperetin, naringenin, and apigenin. Bioinorg. Chem. Appl., 2009. 2009347872
[http://dx.doi.org/10.1155/2009/347872] [PMID: 19830248]
[31]
Thamilarasan, V.; Sethuraman, V.; Karunakaran, P.; Sethupathi, M.; Manisankar, P.; Selvaraju, C.; Sengottuvelan, N. Synthesis, physicochemical properties, thermal analysis and biological application of phosphorescent cationic iridium(III) complexes. Inorganica. Chim. Acta, 2017, 467, 264-275.