Synthesis and structure-activity relationship study: Anticancer chalcones derived from 4′-morpholinoacetophenone

Abstract

The aim of this research was to synthesize chalcone

derivatives containing morpholine ring and to investigate

their antiproliferative activity. The 3-aryl-1-[4-(morpholin-

4-yl)phenyl]prop-2-en-1-one derivatives were synthesized

and evaluated for their in vitro antiproliferative activities

on C6 cells (Rat glioma cell line) and HeLa cells (Human

cervix adenocarcinoma), using the BrdU ELISA assay. The

calculation of ADME properties of new chalcone derivatives

was used by topological polar surface area (TPSA), absorption

(ABS%) and Lipinski’s rules. Most of the compounds exhibited

significantly antiproliferative activity on two cell lines. Among

the screened compounds, compound 7, 10, 11 and 12 revealed

higher antiproliferative activity than cisplatin which was used

as reference drug. Compound 11 on HeLa cell and compound

10 on C6 cell line are the most effective compared with

cisplatin.

Keywords

• Chalcone; antiproliferative activity; cytotoxic; morpholine

References

1. 1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem 2005; 13: 5043-54. 2. Sashidhara KV, Kumar A, Kumar M, Sarkar J, Sinha S. Synthesis and in vitro evaluation of novel coumarin -chalcone hybrids as potential Anticancer agents. Bioorg Med Chem 2010; 24: 7205-11. 3. Hatzade K, Taile V, Gaidhane P, Ingle V. Synthesis, structural determination, and biological activity of new 7-hydroxy-3- pyrazolyl-4H-chromen- 4-ones and their o-b-D-glucosides. Turk J Chem 2010; 34: 241-54. 4. Campos-Buzzi F, Padaratz P, Meira AV, Corrêa R, Nunes RJ, Cechinel-Filho V. 4’-Acetamidochalcone derivatives as potential antinociceptive agents. Molecules 2007; 12: 896-906. 5. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P, Khan SR. Anticancer activities of novel chalcone and bischalcone derivatives. Bioorg Med Chem 2006; 14: 3491-5. 6. Zhang L, Wang X, Wang J, Grinberg N, Krishnamurthy DK, Senanayake CH. An improved method of amide synthesis using acyl chlorides. Tetrahedron Lett 2009; 50: 2964-6. 7. Bandgar BP, Gawande SS, Bodade RG, Gawande NM, Khobragade CN. Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, antioxidant and antimicrobial agents. Bioorg Med Chem 2009;17: 8168-73. 8. Tiwari V, Ali P, Meshram J. Microwave assisted synthesis of 3-(2-chloroguiolin-3-yl)-1-substituted phenyl prop-2-en-1- ones using K2CO3 as a mild, cheap and ınexpensive catalyst. Int J Chem Tech Res 2010; 2: 1031-5. 9. Boeck P, Falcao CAB, Leal PC, Yunes RA, Filho VC, Torres- Santos EC, Rossi-Bergmann B. Synthesis of chalcone analogues with increased antileishmanial activity. Bioorg Med Chem 2006; 14: 1538-45. 10. Ceylan M, Gurdere MB, Karaman I, Gezegen H. Synthesis and screening antimicrobial activities of novel 1,3-diaryl-3- (phenylthio)propan-1-one derivatives. Med Chem Res 2011; 20: 109-15. 11. Mishra N, Arora P, Kumar B, Mishra LC, Bhattacharya A, Awasthi SK, Bhasin VK. Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro. Eur J Med Chem 2008; 43: 1530-5. 12. Wheeler OH, Gore PH, Santiago M, Baez R. Ultraviolet Absorption of Substituted Phenyl and Polycyclic aryl Chalcones. Canadian J Chem 1964; 42: 2580-3. 13. Rizvi SUF, Siddiqui HL, Johns M, Detorio M, Schinazi RF. Anti-HIV-1 and cytotoxicity studies of piperidyl-thienyl chalcones and their 2-pyrazoline derivatives. Med Chem Res 2012; 21: 3741-9. 14. a) Kursun BS, Oruç-Emre EE, Karaküçük-İyidoğan A, Şahin A, Tekin Ş, Demirtaş İ. Antiproliferative activity of the substituted morpholine derivatives chalcone. Turkish Patent Institute, TPE 2011/05601, 2011. b) Kursun BS, Oruç-Emre EE, Karaküçük-İyidoğan A, Şahin A, Tekin Ş, Demirtaş İ. Antiproliferative activity of the substituted morpholine derivatives chalcone. Turkish Patent Institute, TPE 2013/04957, 2013. 15. Demirtas I, Sahin A. Bioactive volatile content of the stem and root of Centaurea carduiformis DC. subsp. carduiformis var. carduiformis. E-J Chem 2012; 2013. 16. Demirtas I, Sahin A, Ayhan B, Tekin S, Telci I. antiproliferative effects of the methanolic extracts of Sideritis libanotica Labill. subsp. linearis. Rec Nat Prod 2009; 3: 104-9. 17. Gopalakrishnan M, Thanusu J, Kanagarajan V, Govindaraju R. Synthesis, antibacterial, and antifungal activities of biolabile (E)-1-(4-morpholinophenyl)-3-aryl-prop-2-en-1- ones. Med Chem Res 2009; 18: 341-50. 18. Silverstein RM, Bassler GC, Merrill TC. Spectrometric Identification of Organic Compounds. John Wiley & Sons,Inc, Singapore. 1991. 19. Palibroda N. Electron ionisation mass spectra of some substituted chalcones. Studia Universitatis Babes-Bolyai, Physica, L 2005; 4b: 34-38. 20. Okwu DE, Ukanwa N. Isolation and characterization of flavonoids chalcones and anthocynidines from bridelia ferruginea benth. Der Chemica Sinica 2010; 1: 21-8. 21. Azev YA, Dülcks T, Gabel D. Cyanuric and thiocyanuric esters as carriers of boron-containing fragments and their fragmentation in mass spectrometry. Tetrahedron Lett 2003; 344: 8689-91. 22. Sato T, Ashizawa N, Iwanaga T, Nakamura H, Matsumoto K, Inoue T, Nagata O. Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl- 1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors. Bioorg Med Chem Lett 2009; 19:184-7. 23. Luzina EL, Popov AV. Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N’-thiazolyl and N-bis(trifluoromethyl)alkyl-N’-benzothiazolyl ureas. Eur J Med Chem 2009; 44: 4944-53. 24. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper I. Rate-limited steps of human oral absorption and QSAR studies. Pharm Res 2012;19: 1446-57.