Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

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

Effective Pharmacophore for CDC25 Phosphatases Enzyme Inhibitors: Newly Synthesized Bromothiazolopyrimidine Derivatives

Author(s): Mahmoud El-Shahat*, Mowafia. A.M. Salama, Ahmed F. El-Farargy, Mamdouh M. Ali and Dalia M. Ahmed

Volume 21, Issue 1, 2021

Published on: 19 June, 2020

Page: [118 - 131] Pages: 14

DOI: 10.2174/1389557520666200619182519

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Thiazolopyrimidine analogues are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity.

Objective: To report the synthesis of novel bromothiazolopyrimidine derivatives and the study of both molecular modeling and in-vitro anticancer activity.

Methods: Novel bromothiazolopyrimidine derivatives 5-18 have been prepared from 2-bromo-3-(4- chlorophenyl)-1-(3,4-dimethylphenyl)-propenone 3 as a key starting compound. The anti-cancer activities of the new compounds were evaluated against HepG2, MCF-7, A549 and HCT116 cell lines.

Results: The compounds 16, 17 and 18 showed cytotoxic and growth inhibitory activities on both colon and lung cells. The cytotoxic activities of the novel synthetic compounds 8, 9, 11, 16, 17 and 18 were due to CDC25 phosphatases inhibition as shown by the enzymatic binding assay. Although compounds 8, 9 and 11 have only demonstrated CDC25B phosphatases inhibition.

Conclusion: The novel bromothiazolopyrimidine derivatives showed promising in vitro anticancer activities against colon cancer HCT116 and lung cancer A549 cell lines comparable to the anticancer drug doxorubicin.

Keywords: Bromothiazolopyrimidines, molecular modeling, CDC25 phosphatases inhibitor, HepG2, MCF-7, A549, HCT116.

« Previous Next »
Graphical Abstract

[1]
Bordo, D.; Bork, P. The rhodanese/Cdc25 phosphatase superfamily. Sequence-structure-function relations. EMBO Rep., 2002, 3(8), 741-746.
[http://dx.doi.org/10.1093/embo-reports/kvf150 ] [PMID: 12151332]
[2]
Boutros, R.; Lobjois, V.; Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat. Rev. Cancer, 2007, 7(7), 495-507.
[http://dx.doi.org/10.1038/nrc2169] [PMID: 17568790]
[3]
Hoffmann, I. The role of Cdc25 phosphatases in cell cycle checkpoints. Protoplasma, 2000, 211(1), 8-11.
[http://dx.doi.org/10.1007/BF01279894]
[4]
Xu, X.; Yamamoto, H.; Sakon, M.; Yasui, M.; Ngan, C.Y.; Fukunaga, H.; Morita, T.; Ogawa, M.; Nagano, H.; Nakamori, S.; Sekimoto, M.; Matsuura, N.; Monden, M. Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin. Cancer Res., 2003, 9(5), 1764-1772.
[5]
Ngan, E.S.W.; Hashimoto, Y.; Ma, Z-Q.; Tsai, M-J.; Tsai, S.Y. Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene, 2003, 22(5), 734-739.
[http://dx.doi.org/10.1038/sj.onc.1206121] [PMID: 12569365]
[6]
Kristjánsdóttir, K.; Rudolph, J. Cdc25 phosphatases and cancer. Chem. Biol., 2004, 11(8), 1043-1051.
[http://dx.doi.org/10.1016/j.chembiol.2004.07.007] [PMID: 15324805]
[7]
Prevost, G.P.; Brezak, M-C.; Goubin, F.; Mondesert, O.; Galcera, M-O.; Quaranta, M.; Alby, F.; Lavergne, O.; Ducommun, B. Inhibitors of the CDC25 phosphatases. Prog. Cell Cycle Res., 2003, 5, 225-234.
[PMID: 14593717]
[8]
Brezak, M-C.; Valette, A.; Quaranta, M.; Contour-Galcera, M-O.; Jullien, D.; Lavergne, O.; Frongia, C.; Bigg, D.; Kasprzyk, P.G.; Prevost, G.P.; Ducommun, B. IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells. Int. J. Cancer, 2009, 124(6), 1449-1456.
[9]
Sarkis, M.; Tran, D.N.; Kolb, S.; Miteva, M.A.; Villoutreix, B.O.; Garbay, C.; Braud, E. Design and synthesis of novel bis-thiazolone derivatives as micromolar CDC25 phosphatase inhibitors: Effect of dimerisation on phosphatase inhibition. Bioorg. Med. Chem. Lett., 2012, 22(24), 7345-7350.
[http://dx.doi.org/10.1016/j.bmcl.2012.10.072] [PMID: 23141909]
[10]
Lavecchia, A.; Di Giovanni, C.; Novellino, E. CDC25 phosphatase inhibitors: An update. Mini Rev. Med. Chem., 2012, 12(1), 62-73.
[http://dx.doi.org/10.2174/138955712798868940] [PMID: 22070688]
[11]
Duval, R.; Kolb, S.; Braud, E.; Genest, D.; Garbay, C. Rapid discovery of triazolobenzylidene-thiazolopyrimidines (TBTP) as CDC25 phosphatase inhibitors by parallel click chemistry and in situ screening. J. Comb. Chem., 2009, 11(6), 947-950.
[http://dx.doi.org/10.1021/cc900140f] [PMID: 19835352]
[12]
Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N.D. Rational drug design for anti-cancer chemotherapy: Multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents. Bioorg. Med. Chem., 2012, 20(15), 4848-4855.
[http://dx.doi.org/10.1016/j.bmc.2012.05.071] [PMID: 22750007]
[13]
Speck-Planche, A.; Dias Soeiro Cordeiro, M.N. Speeding up early drug discovery in antiviral research: A fragment-based in silico approach for the design of virtual anti-hepatitis C leads. ACS Comb. Sci., 2017, 19(8), 501-512.
[http://dx.doi.org/10.1021/acscombsci.7b00039] [PMID: 28437091]
[14]
Flefel, E.M.; El-Sofany, W.I.; El-Shahat, M.; Naqvi, A.; Assirey, E. Synthesis, molecular docking and in vitro screening of some newly synthesized triazolopyridine, pyridotriazine and pyridine-pyrazole hybrid derivatives. Molecules, 2018, 23(10), 2548.
[http://dx.doi.org/10.3390/molecules23102548] [PMID: 30301217]
[15]
Shamroukh, A.H.; El-Shahat, M.; Drabowicz, J.; Ali, M.M.; Rashad, A.E.; Ali, H.S. Anticancer evaluation of some newly synthesized N-nicotinonitrile derivative. Eur. J. Med. Chem., 2013, 69, 521-526.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.005] [PMID: 24095746]
[16]
Flefel, E.M.; Tantawy, W.A.; El-Sofany, W.I.; El-Shahat, M.; El-Sayed, A.A.; Abd-Elshafy, D.N. Synthesis of some new pyridazine derivatives for anti-HAV evaluation. Molecules, 2017, 22(1), 148.
[http://dx.doi.org/10.3390/molecules22010148] [PMID: 28106751]
[17]
El-Sayed, A.A.; Khalil, A.M.; El-Shahat, M.; Khaireldin, N.Y.; Rabie, S.T. Antimicrobial activity of PVC-pyrazolone-silver nanocomposites. J. Macromol. Sci. Part A Pure Appl. Chem., 2016, 53(6), 346-353.
[http://dx.doi.org/10.1080/10601325.2016.1166000]
[18]
El-Sayed, A.; Khaireldin, N.Y.; Elshahat, M.; El-Hefny, E.A.; El-Saidi, M.M.T.; Ali, M.M.; Mahmoud, A.E. Anti proliferative activity for newly heterofunctionalized pyridine analogues. Ponte, 2016, 72, 106-118.
[19]
Abdelhameed, R.M.; El-Sayed, H.A.; El-Shahat, M.; El-Sayed, A.A.; Darwesh, O.M. Novel triazolothiadiazole and triazolothiadiazine derivatives containing pyridine moiety: Design, synthesis, bactericidal and fungicidal activities. Curr. Bioact. Compd., 2018, 14(2), 169-179.
[http://dx.doi.org/10.2174/1573407213666170127095158]
[20]
El-Sayed, A.; El-Shahat, M.; Rabie, S.; Flefel, E.; Abd-Elshafyc, D. New pyrimidine and fused pyrimidine derivatives: Synthesis and anti Hepatitis A virus (HAV) evaluation. Int. J. Pharm., 2015, 5(1), 69-79.
[21]
Soliman, H.A.; El-Shahat, M.; Soliman, A-G. Silica-supported zinc chloride (ZnCl2/SiO2)-induced efficient protocol for the synthesis of N-sulfonyl imines and 2-arylbenzothiazole. Lett. Org. Chem., 2019, 16(7), 584-591.
[http://dx.doi.org/10.2174/1570178615666181025120307]
[22]
Flefel, E.M.; El-Sofany, W.I.; Al-Harbi, R.A.K.; El-Shahat, M. Development of a novel series of anticancer and antidiabetic: Spirothiazolidines analogs. Molecules, 2019, 24(13), 2511.
[http://dx.doi.org/10.3390/molecules24132511] [PMID: 31324043]
[23]
El-Shahat, M.; Abdelhamid, A.E.; Abdelhameed, R.M. Capture of iodide from wastewater by effective adsorptive membrane synthesized from MIL-125-NH2 and cross-linked chitosan. Carbohydr. Polym., 2020.231115742
[http://dx.doi.org/10.1016/j.carbpol.2019.115742] [PMID: 31888810]
[24]
Flefel, E.M.; Sofany, W.I.; Awad, H.M.; Shahat, M.E. First synthesis for Bis-spirothiazolidine derivatives as a novel heterocyclic framework and their biological activity. Mini Rev. Med. Chem., 2019.
[PMID: 31538895]
[25]
Abdelhameed, R.M.; El-Shahat, M. Fabrication of ZIF-67@ MIL-125-NH2 nanocomposite with enhanced visible light photoreduction activity. J. Environ. Chem. Eng., 2019, 7(3)103194
[http://dx.doi.org/10.1016/j.jece.2019.103194]
[26]
Salama, M.; El-Shahat, M.; Elhefny, E.; El-Sayed, A. a novel fused pyridopyrimidine derivatives: Synthesis and characterization. Int. J. Pharm., 2015, 5, 53-58.
[27]
Rashad, A.E.; Shamroukh, A.H.; El-Hashash, M.A.; El-Farargy, A.F.; Yousif, N.M.; Salama, M.A.; Abdelwahed, N.; El-Shahat, M. 1, 3-Bis (4-chlorophenyl)-2, 3-epoxypropanone as synthons in synthesis of some interesting potential antimicrobial agents. Org. Chem. Indian J, 2013, 9, 287.
[28]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[http://dx.doi.org/10.1093/jnci/82.13.1107] [PMID: 2359136]
[29]
Ali, M.M.; Mahmoud, A.E.; Abdel-Halim, A.H.; Fyiad, A.A. Anti-cancer effect of some prepared sulfated oligosaccharides on three different human cancer cell lines. Asian J. Pharm. Clin. Res., 2014, 7(Suppl. 1), 168-176.
[30]
Flefel, E.; Salama, M.; El-Shahat, M.; El-Hashash, M.; El-Farargy, A. A novel synthesis of some new pyrimidine and thiazolopyrimidine derivatives for anticancer evaluation. Phosphorus Sulfur Silicon Relat. Elem., 2007, 182(8), 1739-1756.
[http://dx.doi.org/10.1080/10426500701313912]
[31]
Koska, J.; Spassov, V.Z.; Maynard, A.J.; Yan, L.; Austin, N.; Flook, P.K.; Venkatachalam, C.M. Fully automated molecular mechanics based induced fit protein-ligand docking method. J. Chem. Inf. Model., 2008, 48(10), 1965-1973.
[http://dx.doi.org/10.1021/ci800081s] [PMID: 18816046]
[32]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43(21), 3867-3877.
[http://dx.doi.org/10.1021/jm000292e] [PMID: 11052792]
[33]
Cheng, A.; Dixon, S.L. In silico models for the prediction of dose-dependent human hepatotoxicity. J. Comput. Aided Mol. Des., 2003, 17(12), 811-823.
[http://dx.doi.org/10.1023/B:JCAM.0000021834.50768.c6 ] [PMID: 15124930]

Rights & Permissions Print Cite
Article Metrics
29
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy