Abstract
Novel dimers of triphenylethylene–coumarin hybrid containing two amino side chains were designed and synthesized by the condensation of three dicarboxylic acids with the amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. All the dimeric compounds exhibited significant anti-proliferative activity against four cancer cells at IC50 of near 10 μM, and higher than their corresponding monomeric compounds except compound 9b. Among them, compounds 9a (R = NEt2) linked by sebacamide and 8b (R = piperidinyl) linked by adipamide were the best ones, respectively. UV–Vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that the monomeric compounds 6b and the dimers 7b, 8b, and 9b had significant interactions with Ct-DNA by the intercalative mode of binding. The order of their anti-proliferative activities was 8b > 7b> 6b > 9b, in accordance with that of their DNA binding properties.
Graphical abstract
Novel dimers of triphenylethylene–coumarin hybrid containing two amino side chains were designed and synthesized. All the dimeric compounds exhibited significant anti-proliferative activity against cancer cells. Both the length of the linker and the basic amino group had certain effects on their anti-proliferative activity.
Anticancer activity and DNA binding property of the dimers of triphenylethylene–coumarin hybrid with two amino side chains
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Amin KM, Abdel Gawad NM, Abdel Rahman DE, El Ashry MKM (2014) New series of 6-substituted coumarin derivatives as effective factor Xa inhibitors: synthesis, in vivo antithrombotic evaluation and molecular docking. Bioorg Chem 52:31–43
Avin BRV, Thirusangu P, Ranganatha VL, Firdouse A, Prabhakar BT, Khanum SA (2014) Synthesis and tumor inhibitory activity of novel coumarin analogs targeting angiogenesis and apoptosis. Eur J Med Chem 75:211–221
Bailly C (2012) Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem Rev 112:3611–3640
Basanagouda M, Jambagi VB, Barigidad NN, Laxmeshwar SS, Narayanachar VD (2014) Synthesis, structure-activity relationship of iodinated-4- aryloxymethyl-coumarins as potential anti-cancer and anti-mycobacterial agents. Eur J Med Chem 74:225–233
Belluti F, Fontana G, Dal Bo L, Carenini N, Giommarelli C, Zunino F (2010) Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: identification of novel proapoptotic agents. Bioorg Med Chem Lett 18:3543–3550
Breslow R, Overman IE (1970) “Artificial enzyme” combining a metal catalytic group and a hydrophobic binding cavity. J Am Chem Soc 92:1075–1077
Burlison JA, Blagg BSJ (2006) Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery. Org Lett 8:4855–4858
Chaveerach U, Meenongwa A, Trongpanich Y, Soikum C, Chaveerach P (2010) DNA binding and cleavage behaviors of copper(II) complexes with Amidino-O-methylurea and N-Methylphenyl-amidino-O-methylurea, and their antibacterial activities. Polyhedron 29:731–738
Chen Y, Wang SL, Xu XQ, Liu X, Yu MQ, Zhao S, Liu SC, Qiu YL, Zhang T, Liu BF, Zhang GS (2013a) Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as Potential multireceptor atypical antipsychotics. J Med Chem 56:4671–4690
Chen H, Li S, Yao YC, Zhou LK, Zhao JP, Gu YJ, Wang KR, Li XL (2013b) Design, synthesis, and anti-tumor activities of novel triphenylethylene-coumarin hybrids, and their interactions with Ct-DNA. Bioorg Med Chem Lett 23:4785–4789
Chu CY, Tsai YY, Wang CJ, Lin WL, Tseng TH (2001) Induction of apoptosis by esculetin in human leukemia cells. Eur J Pharmacol 416:25–32
Cuenca F, Greciano O, Gunaratnam M, Haider S, Munnur D, Nanjunda R, Wilson WD, Neidle S (2008) Tri- and tetra-substituted naphthalene diimides as potent G-quadruplex ligands. Bioorg Med Chem Lett 18:1668–1673
Facompre M, Tardy C, Bal MC, Colson P, Perez C, Manzanares I, Cuevas C, Bailly C (2003) Lamellarin D: a novel potent inhibitor of topoisomerase I. Cancer Res 63:7392–7399
Faulhaber K, Granzhan A, Ihmels H, Otto D, Thomas L, Wells S (2011) Studies of the fluorescence light-up effect of amino-substituted benzo[b]quinolizinium derivatives in the presence of biomacromolecules. Photoch Photobio Sci 10:1535–1545
Gupta A, Mandal SK, Leblanc V, Descôeaux C, Asselin É, Bérubé G (2008) Synthesis and cytotoxic activity of benzopyran-based platinum(II) complexes. Bioorg Med Chem Lett 18:3982–3987
Hamulakova S, Janovec L, Hrabinova M, Spilovska K, Korabecny J, Kristian P, Kuca K, Imrich J (2014) Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors. J Med Chem 57:7073–7084
Hwu JR, Lin SY, Tsay SC, De Clercq E, Leyssen P, Neyts J (2011) Coumarin-purine ribofuranoside conjugates as new agents against hepatitis C virus. J Med Chem 54:2114–2126
Jiang X, Shang L, Wang ZX, Dong SJ (2005) Spectrometric and voltammetric investigation of interaction of neutral red with calf thymus DNA: pH effect. Biophys Chem 118:42–50
Kawate T, Iwase N, Shimizu M, Stanley SA, Wellington S, Kazyanskaya E, Hung DT (2013) Synthesis and structure-activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32. Bioorg Med Chem Lett 23:6052–6059
Kusuma BR, Peterson LB, Zhao HP, Vielhauer G, Holzbeierlein J, Blagg BSJ (2011) Targeting the heat shock protein 90 dimer with dimeric inhibitors. J Med Chem 54:6234–6253
Li B, Pai R, Di M, Aiello D, Barnes MH, Butler MM, Tashjian TF, Peet NP, Bowlin TL, Moir DT (2012) Coumarin-based inhibitors of bacillus anthracis and staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities. J Med Chem 55:10896–10908
Liu XH, Liu HL, Chen J, Yang Y, Song BA, Bai LS, Liu JX, Zhu HL, Qi XB (2010) Synthesis and molecular docking study of novel coumarin derivatives containing 4,5-Dihydropyrazole moiety as potential antitumor agents. Bioorg Med Chem Lett 20:5705–5708
Maheswari PU, Palaniandavar M (2004) DNA binding and cleavage activity of [Ru(NH3)4(diimine)]Cl2 complexes. Inorg Chim Acta 357:901–912
McKie JA, Bhagwat SS, Brady H, Doubleday M, Gayo L, Hickman M, Jalluri RK, Khammungkhune S, Kois A, Mortensen D, Richard N, Sapienza J, Shevlin G, Stein B, Sutherland M (2004) Lead identification of a potent benzopyranone selective estrogen receptor modulator. Bioorg Med Chem Lett 14:3407–3410
Micco M, Collie GW, Dale AG, Ohnmacht SA, Pazitna I, Gunaratnam M, Reszka AP, Neidle S (2013) Structure-based design and evaluation of naphthalene diimide G-Quadruplex ligands as telomere targeting agents in pancreatic cancer cells. J Med Chem 56:2959–2974
Mosmann TJ (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Immunol Meth 65:55–63
Nagarajan M, Morrell A, Fort BC, Meckley MR, Antony S, Kohlhagen G, Pommier Y, Mark C (2004) Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings. J Med Chem 47:5651–5661
Nasr T, Bondock S, Youns M (2014) Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives. Eur J Med Chem 76:539–548
Pandey S, Baker GA, Kane MA, Bonzagni NJ, Bright FV (2000) O2 Quenching of ruthenium(II) tris(2,2’-bypyridyl)2+ within the water pool of perfluoropolyether-based reverse micelles formed in supercritical carbon dioxide. Langmuir 16:5593–5599
Pasternack PF, Gibbs FJ, Villatrnaca J (1983) Interactions of porphyrins with nucleic acids. Biochemistry 22:2406–2414
Pérez-Cruz F, Vazquez-Rodriguez S, João Matos M, Herrera-Morales A, Villamena FA, Das A, Gopalakrishnan B, Olea-Azar C, Santana L, Uriarte E (2013) Synthesis and electrochemical and biological studies of novel coumarin-chalcone hybrid compounds. J Med Chem 56:6136–6145
Purcell M, Neault JF, Tajmir-Riahi HA (2000) Interaction of taxol with human serum albumin. Biochim Biophys Acta 1478:61–68
Ramadass R, B-Hahn J (2007) Photophysical properties of DASPMI as revealed by spectrally resolved fluorescence decays. J Phys Chem B 111:7681–7690
Rempel V, Volz N, Gläser F, Nieger M, Bräse S, Müller CE (2013) Antagonists for the orphan G protein-coupled receptor GPR55 based on a coumarin scaffold. J Med Chem 56:4798–4810
Ruiz MC, Chilpa RR, Estrada E, Reyes EJ, Fariña GG, Fragoso LR (2007) Antiproliferative, cytotoxic and antitumour activity of coumarins isolated from calophyllum brasiliense. J Pharm Pharmacol 59:719–725
Sahoo D, Bhattacharya P, Chakravorti S (2010) Reverse micelle induced flipping of binding site and efficiency of albumin protein with an ionic styryl dye. J Phys Chem B 114:10442–10450
Sashidhara KV, Kumar A, Kumar M, Sarkar J, Sinha S (2010) Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents. Bioorg Med Chem Lett 20:7205–7211
Shen Q, Shao JL, Peng Q, Zhang WJ, Ma L, Chan ASC, Gu LQ (2010) Hydroxycoumarin derivatives: novel and potent α-Glucosidase inhibitors. J Med Chem 53:8252–8259
Siddiqui ZN, Mohammed Musthafa TN, Ahmad A, Khan AU (2011) Synthesis of 4-Hydroxycoumarin heteroarylhybrids as potential antimicrobial agents. Arch Pharm Chem Life Sci 344:394–401
Stefanachi A, Favia AD, Nicolotti O, Leonetti F, Pisani L, Catto M, Zimmer C, Hartmann RW, Carotti A (2011) Design, synthesis, and biological evaluation of imidazolyl derivatives of 4,7-Disubstituted coumarins as aromatase inhibitors selective over 17-α-Hydroxylase/C17 − 20 lyase. J Med Chem 54:1613–1625
Tan GH, Yao YC, Gu YJ, Li S, Lv MJ, Wang KR, Chen H, Li XL (2014) Cytotoxicity and DNA binding property of the dimers of triphenylethylene-coumarin hybrid with one amino side chain. Bioorg Med Chem Lett 24:2825–2830
Touisni N, Maresca A, McDonald PC, Lou YM, Scozzafava A, Dedhar S, Winum JY, Supuran CT (2011) Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. J Med Chem 54:8271–8277
Upadhyay K, Bavishi A, Thakrar S, Radadiya A, Vala H, Parekh S, Bhavsar D, Savant M, Parmar M, Adlakha P, Shah A (2011) Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity. Bioorg Med Chem Lett 21:2547–2549
Wan XB, Zhang W, Li L, Xie YT, Li W, Huang N (2013) A New target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling. J Med Chem 56:2619–2629
Wang J, Wang D, Miller EK, Moses D, Bazan GC, Heeger AJ (2000) Photoluminescence of water-soluble conjugated polymers: origin of enhanced quenching by charge transfer. Macromolecules 33:5153–5158
Wang CJ, Hsieh YJ, Chu CY, Lin YL, Tseng TH (2002) Inhibition of cell cycle progression in human leukemia HL-60 cells by esculetin. Cancer Lett 183:163–168
Zhang ZC, Yang YY, Zhang DN, Wang YY, Qian XH, Liu FY (2006) Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators: various DNA binding geometry and interesting antitumor capacity. Bioorg Med Chem 14:6962–6970
Zhang WJ, Li Z, Zhou M, Wu F, Hou XY, Luo H, Liu H, Han X, Yan GY, Ding ZY, Li R (2014) Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents. Bioorg Med Chem Lett 24:799–807
Zhao HP, Donnelly AC, Kusuma BR, Brandt GEL, Brown D, Rajewski R, Vielhauer G, Holzbeierlein J, Cohen MS, Blagg BSJ (2011) Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti- proliferative agents. J Med Chem 54:3839–3853
Zhao L, Yao YC, Li S, Lv MJ, Chen H, Li XL (2014) Cytotoxicity and DNA binding property of triphenylethylene-coumarin hybrids with two amino side chains. Bioorg Med Chem Lett 24:900–904
Zou QL, Fang YY, Zhao YX, Zhao HY, Wang Y, Gu Y, Wu FP (2013) Synthesis and in vitro photocytotoxicity of coumarin derivatives for one- and two-photon excited photodynamic therapy. J Med Chem 56:5288–5294
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The financial supports were from the 973 Program (2010CB534913) and the National Natural Science Foundation of China (NSFC) (20902016).
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Zhu, M., Zhou, L., Yao, Y. et al. Anticancer activity and DNA binding property of the dimers of triphenylethylene–coumarin hybrid with two amino side chains. Med Chem Res 24, 2314–2324 (2015). https://doi.org/10.1007/s00044-014-1296-2
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DOI: https://doi.org/10.1007/s00044-014-1296-2