Design, Synthesis and Molecular Docking Study of N-Heterocyclic Chalcone Derivatives as an Anticancer Agents.
Abstract
The Claisen-Schmidt condensation of 4-(aryl)-aminobenzaldehyde and 2-hydroxyacetophenone resulted in a new series of heterocyclic chalcone (4a-4g) derivatives. Nucleophilic aromatic substitution (SNAr) of 4-fluorobenzaldehyde with heterocycle amines by ultrasonication in the presence of a base and polar aprotic solvent yielded 4-(aryl)-aminobenzaldehydes. Spectral investigations were used to establish the structures of synthesized compounds. The in vitro anti-cancer activity of the synthesized derivative was evaluated against MCF-7 (breast cancer) cells by SRB assay. Compounds 4c, 4b, and 4c have a high affinity for the ER receptor binding site, whereas compounds 4c and 4g have a moderate affinity for the VEGER-2 receptor. The GI50 value of 4c ((E)-1-(2-hydroxyphenyl)-3-(4-(4-methylpiperazin-1-yl)-phenyl) prop-2-en-1-one) was 44.6 uM, while the GI50 value of all other derivatives was greater than 80 uM. These findings lay the groundwork for additional research into the combination's potential uses in cancer therapy.
Keywords:
Claisen-Schmidt condensation, VEGFR-2, breast cancer, SRB assay, chalcone, ultrasonication.DOI
https://doi.org/10.25004/IJPSDR.2022.140111References
Wu JZ, Cheng CC, Shen LL, Wang ZK, Wu SB, Li WL, Chen SH, Zhou RP, Qiu PH. Synthetic chalcones with potent antioxidant ability on H2O2-induced apoptosis in PC12 cells. International journal of molecular sciences. 2014; 15(10):18525-39. Available from: doi. org/10.3390/ijms151018525
Kumar D, Kumar NM, Akamatsu K, Kusaka E, Harada H, Ito T. Synthesis and biological evaluation of indolyl chalcones as antitumor agents. Bioorganic & medicinal chemistry letters. 2010;20(13):3916- 9. Available from: doi.org/10.1016/j.bmcl.2010.05.016
Hayat F, Moseley E, Salahuddin A, Van Zyl RL, Azam A. Antiprotozoal activity of chloroquinoline based chalcones. European journal of medicinal chemistry. 2011; 46(5):1897-905. Available from: doi. org/10.1016/j.ejmech.2011.02.004
Domı́nguez JN, Charris JE, Lobo G, de Domı́nguez NG, Moreno MM, Riggione F, Sanchez E, Olson J, Rosenthal PJ. Synthesis of quinolinyl chalcones and evaluation of their antimalarial ac t iv it y. European journal of medicinal chemist r y. 2001; 36(6):555-560. Available from: doi.org/10.1016/S0223-5234(01) 01245-4
Kotra V, Ganapaty S, Adapa SR. Synthesis of a new series of quinolinyl chalcones as anti-cancer and antiinflammatory agents. Indian J Chem - Sect B Org Med Chem. 2010; 49(8):1109–16. Available from: hdl.handle.net/123456789/10082
Lin YM, Zhou Y, Flavin MT, Zhou LM, Nie W, Chen FC. Chalones and f lavonoids as ant i-t uberculosis agent s. Bioorganic & Medicinal Chemistry. 20021; 10(8):2795-802. Available from: doi. org/10.1016/S0968-0896(02)00094-9
Tran TD, Nguyen TT, Do TH, Huynh TN, Tran CD, Thai KM. Synthesis and antibacterial activity of some heterocyclic chalcone analogues alone and in combination with antibiotics. Molecules. 2012; 17(6):6684-96. Available from: doi.org/10.3390/ molecules17066684
Trivedi JC, Bariwal JB, Upadhyay KD, Naliapara YT, Joshi SK, Pannecouque CC, De Clercq E, Shah AK. Improved and rapid synthesis of new coumarinyl chalcone derivatives and their antiviral activity. Tetrahedron Letters. 2007; 48(48):8472-4. Available from: doi:10.1016/j.tetlet.2007.09.175
Hedaitullah M, Ramanpreet W, Khalid I, Balwan S, Asif H. Pyrazoline synthesis through a chalcone intermediate. International Journal of Drug Regulatory Affairs. 2014; 2(4):59-62.
Jayasooriya RG, Molagoda IM, Park C, Jeong JW, Choi YH, Moon DO, Kim MO, Kim GY. Molecular chemotherapeutic potential of butein: A concise review. Food and Chemical Toxicology. 2018; 112:1-10. Available from: doi.org/10.1016/j.fct.2017.12.028
Li B, Xu N, Wan Z, Ma L, Li H, Cai W, Chen X, Huang Z, He Z. Isobavachalcone exerts antiproliferative and proapoptotic effects on human liver cancer cells by targeting the ERKs/RSK2 signaling pathway. Oncology reports. 2019; 41(6):3355-66. Available from: doi.org/10.3892/or.2019.7090
Wang KL, Yu YC, Hsia SM. Perspectives on the Role of Isoliquiritigenin in Cancer. Cancers. 2021;13(1):1-37. Available from: doi.org/10.3390/ cancers 13010115
Ouyang Y, Li J, Chen X, Fu X, Sun S, Wu Q. Chalcone derivatives: Role in anti-cancer therapy. Biomolecules. 2021; 11(6):1–36. Available from: doi.org/10.3390/biom11060894
Karthikeyan C, Solomon VR, Lee H, Trivedi P. Design, synthesis and biological evaluation of some isatin-linked chalcones as novel anti-breast cancer agents: a molecular hybridization approach. Biomedicine & Preventive Nutrition. 2013; 3(4):325-30. Available from: doi.org/10.1016/j.bionut.2013.04.001
Das M, Manna K. Chalcone scaffold in anti-cancer armamentarium: a molecular insight. Journal of toxicology. 2016; 2016. Available from: doi.org/10.1155/2016/7651047
Hosseinzadeh Z, Ramazani A, Razzaghi-Asl N. Anti-cancer nitrogen-containing heterocyclic compounds. Current Organic Chemistry. 2018; 22(23):2256-79. Available from: DOI: 10.2174/1385272822 666181008142138
Ibata T, Isogami Y, Toyoda J. Aromatic nucleophilic substitution of halobenzenes with amines under high pressure. Bulletin of the Chemical Society of Japan. 1991; 64(1):42-9. Available from: doi. org/10.1246/bcsj.64.42
Mečiarová M, Toma Š, Magdolen P. Ultrasound effect on the aromatic nucleophilic substitution reactions on some haloarenes. Ultrasonics sonochemistry. 2003; 10(4-5):265-70. Available from: doi.org/10.1016/S1350-4177(02)00157-8
Ahmad MR, Sastry VG, Bano N, Anwar S. Synthesis of novel chalcone derivatives by conventional and microwave irradiation methods and their pharmacological activities. Arabian Journal of Chemistry. 2016; 9:S931-5. Available from: doi.org/10.1016/j. arabjc.2011.09.002
Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nature protocols. 2006; 1(3):1112-6. Available from: doi.org/10.1038/nprot.2006.179
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New colorimetric cytotoxicity assay for anticancer-drug screening. JNCI: Journal of the National Cancer Institute. 1990; 82(13):1107-12. Available from:-doi.org/10.1093/jnci/82.13.1107
Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer. 2011; 11(8):597-608. Available from: doi.org/10.1038/nrc3093
Dickson RB, Stancel GM. Chapter 8: Estrogen receptor-mediated processes in normal and cancer cells. JNCI Monographs. 2000; 2000(27):135-45. Available from: doi.org/10.1093/oxfordjournals. jncimonographs.a024237
Chitrala KN, Yeguvapalli S. Prediction and analysis of ligands against estrogen related receptor alpha. Asian Pacific Journal of Cancer Prevention. 2013; 14(4):2371-5. Available from: doi.org/10.7314/ APJCP.2013.14.4.2371
Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR. Vascular endothelial growth factor receptor-2 in breast cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2010; 1806(1):108-21. Available from: doi.org/10.1016/j.bbcan.2010.04.004
Aesoy R, Sanchez BC, Norum JH, Lewensohn R, Viktorsson K, Linderholm B. An autocrine VEGF/VEGFR2 and p38 signaling loop confers resistance to 4-hydroxytamoxifen in MCF-7 breast cancer cells. Molecular Cancer Research. 2008; 6(10):1630-8. Available from: DOI: 10.1158/1541-7786.MCR-07-2172
Published
Abstract Display: 757 
PDF Downloads: 657 
