Browse > Article
http://dx.doi.org/10.13160/ricns.2017.10.3.141

Hologram Quantitative Structure-Activity Relationships Study of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl} Urea Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors  

Keretsu, Seketoulie (Department of Biomedical Sciences, College of Medicine, Chosun University)
Balasubramanian, Pavithra K. (Department of Biomedical Sciences, College of Medicine, Chosun University)
Bhujbal, Swapnil P. (Department of Biomedical Sciences, College of Medicine, Chosun University)
Cho, Seung Joo (Department of Biomedical Sciences, College of Medicine, Chosun University)
Publication Information
Journal of Integrative Natural Science / v.10, no.3, 2017 , pp. 141-147 More about this Journal
Abstract
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis, which is the formation of new blood vessels from pre-existing vessels. Consequently, blocking of the vascular endothelial growth factor receptor (VEGFR-2) by small molecule inhibitors leads to the inhibition of cancer induced angiogenesis. In this study, we performed a two dimensional quantitative structure activity relationship (2D-QSAR) study of 38 N-Phenyl-N'-{4-(4-quinolyloxy) phenyl} urea derivatives as VEGFR-2 inhibitors based on hologram quantitative structure-activity (HQSAR). The model developed showed reasonable $q^2=0.521$ and $r^2=0.932$ values indicating good predictive ability and reliability. The atomic contribution map analysis of most active compound (compound 7) indicates that hydrogen and oxygen atoms in the side chain of ring A and oxygen atom in side chain of ring C contributes positively to the activity of the compounds. The HQSAR model developed and the atomic contribution map can serve as a guideline in designing new compounds for VEGFR-2 inhibition.
Keywords
VEGF Kinase; VEGFR-2; HQSAR; Angiogenesis;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 G. Bold, K.-H. Altmann, J. Frei, M. Lang, P. W. Manley, P. Traxler, B. Wietfeld, J. Bruggen, E. Buchdunger, R. Cozens, S. Ferrari, P. Furet, F. Hofmann, G. Martiny-Baron, J. Mestan, J. Rosel, M. Sills, D. Stover, F. Acemoglu, E. Boss, R. Emmenegger, L. Lasser, E. Masso, R. Roth, C. Schlachter, W. Vetterli, D. Wyss, and J. M. Wood, "New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis", J. Med. Chem., Vol. 43, pp. 2310-2323, 2000.   DOI
2 N. A. G. Lankheet, M. J. X. Hillebrand, H. Rosing, J. H. Schellens, J. H. Beijnen, and A. D. R. Huitema, "Method development and validation for the quantification of dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib and sunitinib in human plasma by liquid chromatography coupled with tandem mass spectrometry", Biomed. Chromatogr., Vol. 27, pp. 466-476, 2013.   DOI
3 T. K. Choueiri, F. A. Schutz, Y. Je, J. E. Rosenberg, and J. Bellmunt, "Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials", J. Clin. Oncol., Vol. 28, pp. 2280-2285, 2010.   DOI
4 H. X. Chen and J. N. Cleck, "Adverse effects of anticancer agents that target the VEGF pathway", Nat. Rev. Clin. Oncology., Vol. 6, pp. 465-477, 2009.   DOI
5 T. Kamba and D. M. McDonald, "Mechanisms of adverse effects of anti-VEGF therapy for cancer", Br. J. cancer, Vol. 96, pp. 1788-1795, 2007.   DOI
6 J. Verma, V. M. Khedkar, and E. C. Coutinho, "3DQSAR in drug design-a review", Curr. Top. Med. Chem, Vol. 10, pp. 95-115, 2010.   DOI
7 A. Z. Dudek, T. Arodz, and J. Galvez, "Computational methods in developing quantitative structureactivity relationships (QSAR): a review", Comb. Chem. high throughput screen., Vol. 9, pp. 213-228, 2006.   DOI
8 H. Zeng and H. Zhang, "Combined 3D-QSAR modeling and molecular docking study on 1, 4-dihydroindeno [1, 2-c] pyrazoles as VEGFR-2 kinase inhibitors", J. Mol. Graph. Model., Vol. 29, pp. 54-71, 2010.   DOI
9 M. M. Neaz, F. A. Pasha, M. Muddassar, S. H. Lee, T. Sim, J.-M. Hah, and S. J. Cho, "Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors", Med. Chem. Res., Vol. 18, pp. 127-142, 2009.   DOI
10 C. Munoz, F. Adasme, J. H. Alzate-Morales, A. Vergara-Jaque, T. Kniess, and J. Caballero, "Study of differences in the VEGFR2 inhibitory activities between semaxanib and SU5205 using 3D-QSAR, docking, and molecular dynamics simulations", J. Mol. Graph. Model., Vol. 32, pp. 39-48, 2012.   DOI
11 K. Kubo, T. Shimizu, S.-I. Ohyama, H. Murooka, A. Iwai, K. Nakamura, K. Hasegawa, Y. Kobayashi, N. Takahashi, K. Takahashi, S. Kato, T. Izawa, and T. Isoe, "Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of n-phenyl-n '-{4-(4-quinolyloxy) phenyl} ureas", J. Med. Chem., Vol. 48, pp. 1359-1366, 2005.   DOI
12 K. J. Kim, B. Li, J. Winer, M. Armanini, N. Gillett, H. S. Phillips, and N. Ferrara, "Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo", Nature, Vol. 362, pp. 841-844, 1993.   DOI
13 J. Folkman, "Anti-angiogenesis: new concept for therapy of solid tumors", Ann. Surg., Vol. 175, pp. 409-416, 1972.   DOI
14 G. Bergers, K. Javaherian, K.-M. Lo, J. Folkman, and D. Hanahan, "Effects of angiogenesis inhibitors on multistage carcinogenesis in mice", Science, Vol. 284, pp. 808-812, 1999.   DOI
15 T.-P. D. Fan, R. Jagger, and R. Bicknell, "Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy", Trends Pharmacol. Sci., Vol. 16, pp. 57-66, 1995.   DOI
16 W. Kolch, G. Martiny-Baron, A. Kieser, and D. Marme, "Regulation of the expression of the VEGF/VPS and its receptors: role in tumor angiogenesis", Breast Cancer Res. Treat., Vol. 36, pp. 139-155, 1995.   DOI
17 W. P. Leenders, "Targetting VEGF in anti-angiogenic and anti-tumour therapy: Where are we now?", Int. J. Exp. Pathol., Vol. 79, pp. 339-346, 1998.
18 C. R. Rodrigues, T. M. Flaherty, C. Springer, J. H. McKerrow, and F. E. Cohen, "CoMFA and HQSAR of acylhydrazide cruzain inhibitors", Bioorg. Med. Chem. Lett., Vol. 12, pp. 1537-1541, 2002.   DOI
19 M. Clark, R. D. Cramer, and N. Van Opdenbosch, "Validation of the general purpose Tripos 5.2 force field", J. Comput. Chem., Vol. 10, pp. 982-1012, 1989.   DOI
20 M. A. Avery, M. Alvim-Gaston, C. R. Rodrigues, E. J. Barreiro, F. E. Cohen, Y. A. Sabnis, and J. R. Woolfrey, "Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies", J. Med. Chem., Vol. 45, pp. 292-303, 2002.   DOI
21 W. Zhu, G. Chen, L. Hu, X. Luo, C. Gui, C. Luo, C. M. Puah, K. Chen, and H. Jiang, "QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR", Bioorg. Med. Chem., Vol. 13, pp. 313-322, 2005.   DOI
22 S. P. Bhujbal, S. Keretsu, and S. J. Cho, "HQSAR study on substituted 1H-pyrazolo [3, 4-b] pyridines derivatives as FGFR kinase antagonists", J. Chosun Natural Sci., Vol. 10, pp. 85-94, 2017.
23 V. G. Ugale, H. M. Patel, and S. J. Surana, "Molecular modeling studies of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors using pharmacophore based 3D QSAR and docking approach", Arabian Journal of Chemistry, Vol. 10, pp. S1980-S2003, 2017.   DOI
24 T. A. T. Fong, L. K. Shawver, L. Sun, C. Tang, H. App, T. J. Powell, Y. H. Kim, R. Schreck, X. Wang, W. Risau, A. Ullrich, K. P. Hirth, and G. McMahon, "SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types", Cancer res, Vol. 59, pp. 99-106, 1999.
25 L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. McMahon, and C. Tang, "Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases", J. Med. Chem., Vol. 41, pp. 2588-2603, 1998.   DOI
26 L. Sun, N. Tran, C. Liang, F. Tang, A. Rice, R. Schreck, K. Waltz, L. K. Shawver, G. McMahon, and C. Tang, "Design, synthesis, and evaluations of substituted 3-[(3-or 4-carboxyethylpyrrol-2-yl) methylidenyl] indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases", J. Med. Chem., Vol. 42, pp. 5120-5130, 1999.   DOI
27 L. F. Hennequin, E. S. Stokes, A. P. Thomas, C. Johnstone, P. A. Ple, D. J. Ogilvie, M. Dukes, S. R. Wedge, J. Kendrew, and J. O. Curwen, "Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors", J. Med. Chem., Vol. 45, pp. 1300-1312, 2002.   DOI