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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Tit Structure-activity Relationship Study and Design of Novel 1, 8- Naphthimide Derivatives as Potential DNA-targeting Chemotherapeutic Agents for Osteosarcoma

Author(s): Zheng Lian, Hongzong Si*, Huanling Xia and Honglin Zhai

Volume 19, Issue 9, 2023

Published on: 23 May, 2023

Page: [906 - 914] Pages: 9

DOI: 10.2174/1573406419666230414144825

Price: $65

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Abstract

Background: 1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which makes it applicable to the design and development of anti-osteosarcoma drugs.

Objective: The aim of this study is to establish a satisfactory model based on 1, 8-naphthimide derivatives that makes reliable prediction as DNA-targeted chemotherapy agents for osteosarcoma.

Methods: All compounds are constructed using ChemDraw software and subsequently optimized using Sybyl software. COMSIA method is used to construct QSAR model with the optimized compound in Sybyl software package. A series of new 1, 8-naphthalimide derivatives are designed and their IC50 values are predicted using the QSAR model. Finally, the newly designed compounds are screened according to IC50 values, and molecular docking experiments are conducted on the top ten compounds of IC50.

Results: The COMSIA model shows that q2 is 0.529 and the optimum number of components is 6. The model has a high r2 value of 0.993 and a low SEE of 0.033, with the F value and the r2 predicted to be 495.841 and 0.996 respectively. The statistical results and verification results of the model are satisfactory. In addition, analyzing the contour maps is conducive to finding the structural requirements.

Conclusion: The results of this study can provide guidance for medical chemists and other related workers to develop targeted chemotherapy drugs for osteosarcoma.

Keywords: Osteosarcoma, tumor targeting agents, QSAR, COMSIA, drug design, 1, 8-naphthimide.

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[1]
Fan, T.M. Animal models of osteosarcoma. Expert Rev. Anticancer Ther., 2010, 10(8), 1327-1338.
[http://dx.doi.org/10.1586/era.10.107] [PMID: 20735317]
[2]
Anninga, J.K.; Gelderblom, H.; Fiocco, M.; Kroep, J.R.; Taminiau, A.H.M.; Hogendoorn, P.C.W.; Egeler, R.M. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur. J. Cancer, 2011, 47(16), 2431-2445.
[http://dx.doi.org/10.1016/j.ejca.2011.05.030] [PMID: 21703851]
[3]
Botter, S.M.; Neri, D.; Fuchs, B. Recent advances in osteosarcoma. Curr. Opin. Pharmacol., 2014, 16, 15-23.
[http://dx.doi.org/10.1016/j.coph.2014.02.002] [PMID: 24632219]
[4]
Longhi, A.; Ferrari, S.; Bacci, G.; Specchia, S. Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs, 2007, 18(6), 737-744.
[http://dx.doi.org/10.1097/CAD.0b013e32803d36fe] [PMID: 17762406]
[5]
Ando, K.; Mori, K.; Corradini, N.; Redini, F.; Heymann, D. Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin. Pharmacother., 2011, 12(2), 285-292.
[http://dx.doi.org/10.1517/14656566.2011.543129] [PMID: 21226638]
[6]
Baker, P.D.; Morzorati, S.L.; Ellett, M.L. The pathophysiology of chemotherapy-induced nausea and vomiting. Gastroenterol. Nurs., 2005, 28(6), 469-480.
[http://dx.doi.org/10.1097/00001610-200511000-00003] [PMID: 16418583]
[7]
Hurley, L.H. DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer, 2002, 2(3), 188-200.
[http://dx.doi.org/10.1038/nrc749] [PMID: 11990855]
[8]
Skladanowski, A.; Bozko, P.; Sabisz, M. DNA structure and integrity checkpoints during the cell cycle and their role in drug targeting and sensitivity of tumor cells to anticancer treatment. Chem. Rev., 2009, 109(7), 2951-2973.
[http://dx.doi.org/10.1021/cr900026u] [PMID: 19522503]
[9]
Hengartner, M.O. The biochemistry of apoptosis. Nature, 2000, 407(6805), 770-776.
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[10]
Bloodgood, B.L.; Sharma, N.; Browne, H.A.; Trepman, A.Z.; Greenberg, M.E. The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature, 2013, 503(7474), 121-125.
[http://dx.doi.org/10.1038/nature12743] [PMID: 24201284]
[11]
Banerjee, S.; Veale, E.B.; Phelan, C.M.; Murphy, S.A.; Tocci, G.M.; Gillespie, L.J.; Frimannsson, D.O.; Kelly, J.M.; Gunnlaugsson, T. Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents. Chem. Soc. Rev., 2013, 42(4), 1601-1618.
[http://dx.doi.org/10.1039/c2cs35467e] [PMID: 23325367]
[12]
Lv, M.; Xu, H. Overview of naphthalimide analogs as anticancer agents. Curr. Med. Chem., 2009, 16(36), 4797-4813.
[http://dx.doi.org/10.2174/092986709789909576] [PMID: 19929786]
[13]
Hansch, C.; Hoekman, D.; Gao, H. Comparative QSAR: Toward a Deeper Understanding of Chemicobiological Interactions. Chem. Rev., 1996, 96(3), 1045-1076.
[http://dx.doi.org/10.1021/cr9400976] [PMID: 11848780]
[14]
Dearden, J.C. The history and development of quantitative structure-activity relationships (QSARs). Int. j. quant. struct. prop. relatsh., 2016, 1(1)
[http://dx.doi.org/10.4018/IJQSPR.2016010101]
[15]
Roy, K.; Kar, S.; Ambure, P. On a simple approach for determining applicability domain of QSAR models. Chemom. Intell. Lab. Syst., 2015, 145, 22-29.
[http://dx.doi.org/10.1016/j.chemolab.2015.04.013]
[16]
Liang, G.B.; Wei, J.H.; Jiang, H.; Huang, R.Z.; Qin, J.T.; Wang, H.L.; Wang, H.S.; Zhang, Y. Design, synthesis and antitumor evaluation of new 1,8-naphthalimide derivatives targeting nuclear DNA. Eur. J. Med. Chem., 2021, 210, 112951.
[http://dx.doi.org/10.1016/j.ejmech.2020.112951] [PMID: 33109400]
[17]
Yu, Z.; Li, X.; Ge, C.; Si, H.; Cui, L.; Gao, H.; Duan, Y.; Zhai, H. 3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines. Mol. Divers., 2015, 19(1), 135-147.
[http://dx.doi.org/10.1007/s11030-014-9556-0] [PMID: 25355276]
[18]
Ai, Y.; Wang, S-T.; Tang, C.; Sun, P-H.; Song, F-J. 3D-QSAR and docking studies on pyridopyrazinones as BRAF inhibitors. Med. Chem. Res., 2011, 20(8), 1298-1317.
[http://dx.doi.org/10.1007/s00044-010-9468-1]
[19]
Patel, P.D.; Patel, M.R.; Kaushik-Basu, N.; Talele, T.T. 3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors. J. Chem. Inf. Model., 2008, 48(1), 42-55.
[http://dx.doi.org/10.1021/ci700266z] [PMID: 18076152]
[20]
Li, Y.; Wang, Y.H.; Yang, L.; Zhang, S-W.; Liu, C-H.; Yang, S-L. Comparison of steroid substrates and inhibitors of P-glycoprotein by 3D-QSAR analysis. J. Mol. Struct., 2005, 733(1-3), 111-118.
[http://dx.doi.org/10.1016/j.molstruc.2004.08.012]
[21]
Li, X.; Ye, L.; Wang, X.; Wang, X.; Liu, H.; Qian, X.; Zhu, Y.; Yu, H. Molecular docking, molecular dynamics simulation, and structure-based 3D-QSAR studies on estrogenic activity of hydroxylated polychlorinated biphenyls. Sci. Total Environ., 2012, 441, 230-238.
[http://dx.doi.org/10.1016/j.scitotenv.2012.08.072] [PMID: 23137989]
[22]
Yang, W.; Shen, S.; Mu, L.; Yu, H. Structure-activity relationship study on the binding of PBDEs with thyroxine transport proteins. Environ. Toxicol. Chem., 2011, 30(11), 2431-2439.
[http://dx.doi.org/10.1002/etc.645] [PMID: 21842493]
[23]
Rännar, S.; Geladi, P.; Lindgren, F.; Wold, S. A PLS kernel algorithm for data sets with many variables and few objects. Part II: Cross‐validation, missing data and examples. J. Chemometric., 1995, 9(6), 459-470.
[24]
Yang, Y.; Qin, J.; Liu, H.; Yao, X. Molecular dynamics simulation, free energy calculation and structure-based 3D-QSAR studies of B-RAF kinase inhibitors. J. Chem. Inf. Model., 2011, 51(3), 680-692.
[http://dx.doi.org/10.1021/ci100427j] [PMID: 21338122]
[25]
Mouchlis, V.D.; Melagraki, G.; Mavromoustakos, T.; Kollias, G.; Afantitis, A. Molecular modeling on pyrimidine-urea inhibitors of TNF-α production: An integrated approach using a combination of molecular docking, classification techniques, and 3D-QSAR CoMSIA. J. Chem. Inf. Model., 2012, 52(3), 711-723.
[http://dx.doi.org/10.1021/ci200579f] [PMID: 22360289]
[26]
Pratim Roy, P.; Paul, S.; Mitra, I.; Roy, K. On two novel parameters for validation of predictive QSAR models. Molecules, 2009, 14(5), 1660-1701.
[http://dx.doi.org/10.3390/molecules14051660] [PMID: 19471190]
[27]
Li, X.; Ye, L.; Wang, X.; Wang, X.; Liu, H.; Zhu, Y.; Yu, H. Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β. Toxicol. Appl. Pharmacol., 2012, 265(3), 300-307.
[http://dx.doi.org/10.1016/j.taap.2012.08.030] [PMID: 22982074]
[28]
Mao, Y.; Li, Y.; Hao, M.; Zhang, S.; Ai, C. Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors. J. Mol. Model., 2012, 18(5), 2185-2198.
[http://dx.doi.org/10.1007/s00894-011-1236-8] [PMID: 21947448]

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