Pyrimidine Derivatives as Promising Candidates for Potent Antiangiogenic: A silico Study
Keywords:1,2,3-seleniadiazole; Anti-angiogenesis; Anticancer; binding energy; Pyrimidine.
Objectives This study planned to explore the effect of many synthetic compounds derived from(4-chloro-6-methoxy-N,N-dimethylpyrimidin-2-amine) as antiangiogenic.
Methods Docking study has been done by using Molecular Operating Environment (2019) to examine the energy binding affinity of tested compounds with VEGFR-2 kinase and using Discovery Studio Visualizer v22.214.171.12495 free version to visualize the surface binding cavity.
Results Theoretical calculation of these compounds showed significant results in comparing to the reference drug compounds, compound (1) which is 4-(4-(1,2,3-selenadiazol-4-yl)phenoxy)-6-methoxy-N,N-dimethylpyrimidin-2-amine gives the lowest binding energy equal to (-8.116) Kcal/mol and nearest to the reference drug compound, and also it has excellent RMSD equal to (0.9263). The other compounds 4-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-6-methoxy-N,N-dimethylpyrimidin-2-amine, 4-methoxy-N,N-dimethyl-6-(phenylthio)pyrimidin-2-amine, 4-(benzo[d]thiazol-2-ylthio)-6-methoxy-N,N-dimethylpyrimidin-2-amine have -7.739, -7.211 and -7.841 Kcal/mol binding energy and 2.668, 1.745 and 1.377 RMSD respectively.
Conclusion Compound (1) can be recommended as a powerful antiangiogenic due to its theoretical results for binding energy.
2. Tanimoto K, Yoshiga K, Eguchi H, et al. Hypoxia-inducible factor-1Î± polymorphisms associated with enhanced transactivation capacity, implying clinical significance. Carcinogenesis 2003; 24: 1779â€“1783.
3. Tischer E, Gospodarowicz D, Mitchell R, et al. Vascular endothelial growth factor: A new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun 1989; 165: 1198â€“1206.
4. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989; 161: 851â€“858.
5. Connolly DT, Heuvelman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 1989; 84: 1470â€“1478.
6. Leung DW, Cachianes G, Kuang W-J, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science (80- ) 1989; 246: 1306â€“1309.
7. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23: 1011â€“1027.
8. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 2020; 77: 1745â€“1770.
9. Jain RK. Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia. Cancer Cell 2014; 26: 605â€“622.
10. Ferrara N, Hillan KJ, Gerber H-P, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3: 391â€“400.
11. Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci 2015; 36: 422â€“439.
12. Fargualy AM, Habib NS, Ismail KA, et al. Synthesis, biological evaluation and molecular docking studies of some pyrimidine derivatives. Eur J Med Chem 2013; 66: 276â€“295.
13. Sharma V, Chitranshi N, Agarwal AK. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem 2014; 2014: 202784.
14. Habib NS, Soliman R, Ismail K, et al. Pyrimidines. Part II: Synthesis of novel pyrimidines, 1,2,4-triazolo[4,3-a]pyrimidin-7-ones and pyrimidino[2,1-c][1,2,4]triazin-8-ones for their antimicrobial and anticancer activities. Boll Chim Farm 2003; 142: 396â€”405.
15. Kumar S, Deep A, Narasimhan B. A review on synthesis, anticancer and antiviral potentials of pyrimidine derivatives. Curr Bioact Compd 2019; 15: 289â€“303.
16. Ram VJ, Berghe DAV, Vlietinck AJ. 5â€Cyanoâ€6â€aryluracil and 2â€thiouracil derivatives as potential chemotherapeutic agents. IV. Journal of Heterocyclic Chemistry 1984; 21: 1307â€“1312.
17. Mallikarjunaswamy C. Studies on synthesis of pyrimidine derivatives and their antimicrobial activity. Arab J Chem 2017; 10: S484â€“S490.
18. Liu P, Yang Y, Tang Y, et al. Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents. Eur J Med Chem 2019; 163: 169â€“182.
19. Singh K, Kaur T. Pyrimidine-based antimalarials: Design strategies and antiplasmodial effects. Medchemcomm 2016; 7: 749â€“768.
20. Naik NS, Shastri LA, Chougala BM, et al. Synthesis of novel aryl and coumarin substituted pyrazolo[1,5-a]pyrimidine derivatives as potent anti-inflammatory and anticancer agents. Chem Data Collect 2020; 30: 100550.
21. Rani J, Kumar S, Saini M, et al. Biological potential of pyrimidine derivatives in a new era. Res Chem Intermed 2016; 42: 6777â€“6804.
22. McGuigan C, Barucki H, Blewett S, et al. Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain. J Med Chem 2000; 43: 4993â€“4997.
23. Luo M, Groaz E, Snoeck R, et al. Amidate Prodrugs of O-2-Alkylated Pyrimidine Acyclic Nucleosides Display Potent Anti-Herpesvirus Activity. ACS Med Chem Lett 2020; 11: 1410â€“1415.
24. Jafar NNA, Mahdi IMA, Hadwan MH, et al. The antifungal effect of some 4-chloro-6-methoxy-N, N-dimethylpyrimidin-2-amine derivatives containing a heterocyclic compound on the important types of fungi. J Young Pharm 2017; 9: 463â€“467.
25. Lalezari I, Shafiee A, Yazdany S. Selenium heterocycles X: Synthesis and antibacterial activity of pyridylâ€1,2,3â€thiadiazoles and pyridylâ€1,2,3â€selenadiazoles. J Pharm Sci 1974; 63: 628â€“629.
26. Al-Smadi M, Al-Momani F. Synthesis, characterization and antimicrobial activity of new 1,2,3-selenadiazoles. Molecules 2008; 13: 2740â€“2749.
27. Karnik A V., Kulkarni AM, Malviya NJ, et al. Synthesis and in vitro anti-bacterial evaluation of tetracyclic-ortho-fused 4H-naphtho[1â€²,2â€²-5,6]pyrano[3,4-d](1,2,3)selenadiazole and its derivatives. Eur J Med Chem 2008; 43: 2615â€“2617.
28. Gawad J, Bonde C. Design, synthesis and biological evaluation of some 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives as selective DprE1 inhibitors. Synth Commun 2019; 49: 2696â€“2708.
29. Rajendran N, Kamatchi N, Periyasamy A, et al. DNA-interaction, antibacterial and in vitro cytotoxic properties of copper(II) complexes bearing (E)-2-(2-(benzo[d]thiazol-2-ylthio)-1-phenylethylidene)thiosemicarbazone and diimine co-ligands. J Coord Chem 2020; 73: 969â€“985.
30. Gularte MS, Anghinoni JM, Abenante L, et al. Synthesis of chitosan derivatives with organoselenium and organosulfur compounds: Characterization, antimicrobial properties and application as biomaterials. Carbohydr Polym 2019; 219: 240â€“250.
31. Singer C, Kaplan MH, Armstrong D. Bacteremia and fungemia complicating neoplastic disease. A study of 364 Cases. Am J Med 1977; 62: 731â€“742.
32. Inc. CCG. Molecular operating environment (MOE).
33. Biovia DS. BIOVIA workbook, release 2017; BIOVIA pipeline pilot, release 2017. San Diego Dassault SystÃ¨mes.
34. Ghanem A, Emara HA, Muawia S, et al. Tanshinone IIA synergistically enhances the antitumor activity of doxorubicin by interfering with the PI3K/AKT/mTOR pathway and inhibition of topoisomerase II:: In vitro and molecular docking studies. New J Chem 2020; 44: 17374â€“17381.
35. Zaki AA, Al-Karmalawy AA, El-Amier YA, et al. Molecular docking reveals the potential of Cleome amblyocarpa isolated compounds to inhibit COVID-19 virus main protease. New J Chem 2020; 44: 16752â€“16758.
36. Marrone T, Hu-Lowe D, Grazzini M, et al. PF-00337210, a potent, selective and orally bioavailable small molecule inhibitor of VEGFR-2.
37. Ghanem A, Emara HA, Muawia S, et al. Tanshinone IIA synergistically enhances the antitumor activity of doxorubicin by interfering with the PI3K/AKT/mTOR pathway and inhibition of topoisomerase II: in vitro and molecular docking studies. New J Chem.
38. Amin LHT, Shawer TZ, El-Naggar AM, et al. Design, synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors. Bioorg Chem 2019; 91: 103159.