Abstract
A series of twelve pyrazol-3-one Schiff`s base derivatives (5–17) were designed and synthesized by microwave-assisted chemical synthesis. Their purity was confirmed by melting point and HPLC and their chemical structures were determined by FT-IR, UV, 1H, and 13C-NMR spectroscopic techniques. In silico docking of the synthesized compounds inside the active site of thymidine phosphorylase was performed using two molecular modeling programs. The compounds were tested in vitro on calf thymus DNA to study the interaction with DNA using a spectrophotometer. Some of the pyrazol-3-one Schiff`s base derivatives showed close match interaction with DNA. The tested compounds were also studied by application to angiogenic enzyme thymidine phosphorylase (TP, E.C. 2.4.2.4), carcinoma cell lines including both human breast (MCF-7) and human lung cell lines (A549). The lead compound 2 in the series caused inhibition of thymidine phosphorylase in the micro molar range (IC50 of 28 ± 2 µM) and was able to retard growing of breast carcinoma cells. Our results indicate that pyrazol-3-one Schiff base derivatives are promising lead compounds for the development of more active antitumor agents and exhibit their highest cytotoxic effect on breast carcinoma cell line.
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Abbreviations
- 1H-NMR:
-
Proton nuclear magnetic resonance
- HPLC:
-
High performance liquid chromatography
- TP:
-
Thymidine phosphorylase
References
Alam MS, Choi JH, Lee DU (2012) Synthesis of novel Schiff base analogues of 4-amino-1,5-dimethyl-2-phenylpyrazol-3-one and their evaluation for antioxidant and anti-inflammatory activity. Bioorg Med Chem 20:4103–4108
Ali Parvez, Meshram Jyotsna, Sheikh Javed, Tiwari Vandana, Dongre Rajendra, Hadda Taibi Ben (2012) Predictions and correlations of structure activity relationship of some aminoantipyrine derivatives on the basis of theoretical and experimental ground. Med Chem Res 21:157–164
Asiri AM, Khan SA (2010) Synthesis and anti-bacterial activities of some novel Schiff bases derived from aminophenazone. Molecules 15:6850–6858
Balzarini J, Gamboa AE, Esnouf R, Liekens S, Neyts J, De Clercq E, Camarasa MJ, Perez-Perez MJ (1998) 7-Deazaxanthine, a novel prototype inhibitor of thymidine phosphorylase. FEBS Lett 438:91–95
Bera H, Tan BJ, Sun L, Dolzhenko AV, Chui WK, Chiu GN (2013) A structure-activity relationship study of 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues on anti-thymidine phosphorylase and associated anti-angiogenic activities. Eur J Med Chem 67C:325–334
Brockenbrough JS, Morihara JK, Hawes SE, Stern JE, Rasey JS, Wiens LW, Feng Q, Vesselle H (2009) Thymidine kinase 1 and thymidine phosphorylase expression in non-small-cell lung carcinoma in relation to angiogenesis and proliferation. J Histochem Cytochem 57:1087–1097
Caifeng B, Yuhua F (2004) Synthesis and thermodecomposition kinetics of the UO2 (II) complex with 4-(2-hydroxy-naphthalen-1-ylmethyleneamino)-antipyrin. J Radioanal Nucl Chem 262:497–500
Carney P, O’Neill S, O’Neill C (2013) Determinants of breast cancer screening uptake in women, evidence from the British Household Panel Survey. Soc Sci Med 82:108–114
Chohan ZH, Mahmood UH, Khan KM, Supuran CT (2005) In-vitro antibacterial, antifungal and cytotoxic properties of sulfonamide-derived Schiff’s bases and their metal complexes. J Enzym Inhib Med Chem 20:183–188
Cole C, Reigan P, Gbaj A, Edwards PN, Douglas KT, Stratford IJ, Freeman S, Jaffar M (2003) Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: inhibitors of the angiogenic enzyme thymidine phosphorylase. J Med Chem 46:207–209
Doussis-Anagnostopoulou IA, Remadi S, Turley H, Gindre P, Comley M, Borisch B, Gatter KC (1997) Platelet-derived endothelial cell growth factor/thymidine phosphorylase immunohistochemical expression in lymphoid tissue and lymphoid malignancies. Hum Pathol 28:1146–1151
El Sonbati AZ, Diab MA, El Bindary AA, Abd El-Kader MK (2012) Supramolecular and structural modification on conformational by mixed ligand. Spectrochim Acta A Mol Biomol Spectrosc 99:211–217
Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5:1359–1364
Gbaj A, Edwards PN, Reigan P, Freeman S, Jaffar M, Douglas KT (2006) Thymidine phosphorylase from Escherichia coli: tight-binding inhibitors as enzyme active-site titrants. J Enzym Inhib Med Chem 21:69–73
Gelao L, Criscitiello C, Fumagalli L, Locatelli M, Manunta S, Esposito A, Minchella I, Goldhirsch A, Curigliano G (2013) Tumour dormancy and clinical implications in breast cancer. Ecancermedicalscience 7:320
Ghosh P, Devi GP, Priya R, Amrita A, Sivaramakrishna A, Babu S, Siva R (2013) Spectroscopic and in silico evaluation of interaction of DNA with six anthraquinone derivatives. Appl Biochem Biotechnol 170:1127–1137
Haj HT, Salerno M, Priebe W, Kozlowski H, Garnier-Suillerot A (2003) New findings in the study on the intercalation of bisdaunorubicin and its monomeric analogues with naked and nucleus DNA. Chem Biol Interact 145:349–358
Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4:806–813
Hökelek T, Işiklan M, Kiliç Z (2001) 4-{[(1E)-(2-Hydroxyphenyl)methylidene]amino}-1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one. Acta Crystallogr Sect E C57:117–119
Khan KM, Ambreen N, Hussain S, Perveen S, Choudhary MI (2009) Schiff bases of 3-formylchromone as thymidine phosphorylase inhibitors. Bioorg Med Chem 17:2983–2988
Lal A, Panos R, Marjanovic M, Walker M, Fuentes E, Kubicek GJ, Henner WD, Buturovic LJ, Halks-Miller M (2013) A gene expression profile test to resolve head & neck squamous versus lung squamous cancers. Diagn Pathol 8:44
Langen P, Etzold G, Barwolff D, Preussel B (1967) Inhibition of thymidine phosphorylase by 6-aminothymine and derivatives of 6-aminouracil. Biochem Pharmacol 16:1833–1837
Li X (2008) Tes, a potential Mena-related cancer therapy target. Drug Discov Ther 2:1
Li ZX, Zhang XL (2005) 1,5-Dimethyl-2-phenyl-4-[(E, E)-3-phenylprop-2-enylideneamino]-1H-pyrazol-3(2H)-one. Acta Crystallogr Sect E E61:375–377
Liekens S, De Clercq E, Neyts J (2001) Angiogenesis: regulators and clinical applications. Biochem Pharmacol 61:253–270
Maria Negoiui, Simona Pasculescu, Tudor Rosu, Rodica Georgescu, Constantin Draghici (2010) Synthesis and Characterisation of complex Cu(II) combinations with Schiff base ligands derived from 4-amino-1-phenyl-2,3-dimethyl-3-pyrazole-5-one (4-amino-antipyrine) and Pentaatomic Heterocyclic Aldehydes. Rev Chim 1:762–766
Martinez R, Chacon-Garcia L (2005) The search of DNA-intercalators as antitumoral drugs: what it worked and what did not work. Curr Med Chem 12:127–151
Matsushita S, Nitanda T, Furukawa T, Sumizawa T, Tani A, Nishimoto K, Akiba S, Miyadera K, Fukushima M, Yamada Y, Yoshida H, Kanzaki T, Akiyama S (1999) The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors. Cancer Res 59:1911–1916
Mitsiki E, Papageorgiou AC, Iyer S, Thiyagarajan N, Prior SH, Sleep D, Finnis C, Acharya KR (2009) Structures of native human thymidine phosphorylase and in complex with 5-iodouracil. Biochem Biophys Res Commun 386:666–670
Moghaddam A, Choudhouri R, Bicknell R (1997) Tumour angiogenesis. Oxford University Press, Oxford
Mohamed SS, Tamer AR, Bensaber SM, Jaeda MI, Ermeli NB, Allafi AA, Mrema IA, Erhuma M, Hermann A, Gbaj AM (2013) Design, synthesis, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticancer agents. Naunyn Schmiedeberg’s Arch Pharmacol 386:813–822
Nakajima Y, Gotanda T, Uchimiya H, Furukawa T, Haraguchi M, Ikeda R, Sumizawa T, Yoshida H, Akiyama S (2004) Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose. Cancer Res 64:1794–1801
Nascimento-Junior NM, Mendes TC, Leal DM, Correa CM, Sudo RT, Zapata-Sudo G, Barreiro EJ, Fraga CA (2010) Microwave-assisted synthesis and structure-activity relationships of neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives. Bioorg Med Chem Lett 20:74–77
O’Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL (1995) Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 55:510–513
Oezcelik A, Ayazi S, DeMeester SR, Zehetner J, Abate E, Dunn J, Grant KS, Lipham JC, Hagen JA, DeMeester TR (2013) Adenocarcinoma of the esophagus in the young. J Gastrointest Surg 17:1032–1035
Penthala NR, Yerramreddy TR, Crooks PA (2010) Microwave assisted synthesis and in vitro cytotoxicities of substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones against human tumor cell lines. Bioorg Med Chem Lett 20:591–593
Perignon JL, Bories DM, Houllier AM, Thuillier L, Cartier PH (1987) Metabolism of pyrimidine bases and nucleosides by pyrimidine-nucleoside phosphorylases in cultured human lymphoid cells. Biochim Biophys Acta 928:130–136
Pugmire MJ, Ealick SE (1998) The crystal structure of pyrimidine nucleoside phosphorylase in a closed conformation. Structure 6:1467–1479
Puppin C, Puglisi F, Pandolfi M, Di Loreto C, Damante G (2011) Histone deacetylase inhibitors induce thymidine phosphorylase expression in cultured breast cancer cell lines. Oncol Rep 26:309–314
Reigan P, Gbaj A, Chinje E, Stratford IJ, Douglas KT, Freeman S (2004) Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase. Bioorg Med Chem Lett 14:5247–5250
Reigan P, Edwards PN, Gbaj A, Cole C, Barry ST, Page KM, Ashton SE, Luke RW, Douglas KT, Stratford IJ, Jaffar M, Bryce RA, Freeman S (2005) Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs. J Med Chem 48:392–402
Smith G, Sala R, Carroll L, Behan K, Glaser M, Robins E, Nguyen QD, Aboagye EO (2012) Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. Nucl Med Biol 39:652–665
Snyder RD (2007) Assessment of atypical DNA intercalating agents in biological and in silico systems. Mutat Res 623:72–82
Stewart M, Talks K, Leek R, Turley H, Pezzella F, Harris A, Gatter K (2002) Expression of angiogenic factors and hypoxia inducible factors HIF 1, HIF 2 and CA IX in non-Hodgkin’s lymphoma. Histopathology 40:253–260
Suh D, Chaires JB (1995) Criteria for the mode of binding of DNA binding agents. Bioorg Med Chem 3:723–728
Sun NB, Fu JQ, Weng JQ, Jin JZ, Tan CX, Liu XH (2013) Microwave assisted synthesis, antifungal activity and DFT theoretical study of some novel 1,2,4-triazole derivatives containing the 1,2,3-thiadiazole moiety. Molecules 18:12725–12739
Tiffeneau M (1914) Bulletin des Sciences Pharmacologiques 21:71–73
Vaghasiya YK, Nair R, Soni M, Baluja S, Chanda S (2004) Synthesis, structural determination and antibacterial activity of compounds derived from vanillin and 4-aminoantipyrine. J Serb Chem Soc 69:991–998
Voytek P (1975) Purification of thymidine phosphorylase from Escherichia coli and its photoinactivation in the presence of thymine, thymidine, and some halogenated analogs. J Biol Chem 250:3660–3665
Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979–1986
Yang MH, Yan GB, Zheng YF, Zhang CF (2006) (E)-1, 5-Dimethyl-4-(4-methylbenzylideneamino)-2-phenyl-1H-pyrazol-3(2H)-one. Acta Cryst E62:o4944–o4945
Yano S, Kazuno H, Sato T, Suzuki N, Emura T, Wierzba K, Yamashita J, Tada Y, Yamada Y, Fukushima M, Asao T (2004a) Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase. Bioorg Med Chem 12:3443–3450
Yano S, Kazuno H, Suzuki N, Emura T, Wierzba K, Yamashita J, Tada Y, Yamada Y, Fukushima M, Asao T (2004b) Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: discovery of novel orally active inhibitors of human thymidine phosphorylase. Bioorg Med Chem 12:3431–3441
Yin H, Xu Y, Qian X (2007) Novel antitumor agent family of 1H-benzo[c, d]indol-2-one with flexible basic side chains: synthesis and biological evaluation. Bioorg Med Chem 15:1356–1362
You ZL, Wang J, Chi JY (2006) 4-{[(2-Hydroxy-1-naphthyl)methylidene]amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one. Acta Crystallogr Sect E E62:1652–1653
Yu EJ, Lee Y, Rha SY, Kim TS, Chung HC, Oh BK, Yang WI, Noh SH, Jeung HC (2008) Angiogenic factor thymidine phosphorylase increases cancer cell invasion activity in patients with gastric adenocarcinoma. Mol Cancer Res 6:1554–1566
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The authors would like to express their gratitude and thanks to Eng. Jamal Fituri for providing the chemicals. We are also thankful to Sir Ashor Al-Fazany for his valuable technical assistance.
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Bensaber, S.M., Allafe, H.A., Ermeli, N.B. et al. Chemical synthesis, molecular modelling, and evaluation of anticancer activity of some pyrazol-3-one Schiff base derivatives. Med Chem Res 23, 5120–5134 (2014). https://doi.org/10.1007/s00044-014-1064-3
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DOI: https://doi.org/10.1007/s00044-014-1064-3