Synthesis, biological evaluation, and molecular docking studies of substituted chromone-2-carboxamide derivatives as anti-breast cancer agents

Gangapuram, Madhavi; Ghaffari, Mohammad A.; Eyunni, Suresh; Mochona, Bereket; Redda, Kinfe Ken

doi:10.1515/chem-2025-0176

Abstract

Breast cancer is the second leading cause of mortality among women, accounting for 12.5% of all new cancer cases worldwide. By 2030, the estimated number of deaths will escalate to 11.4 million. The research objective is to design and synthesize safe and effective anti-breast cancer agents. A series of substituted chromone-2-carboxamide derivatives (5a–n) were synthesized in moderate to high yields. These compounds’ (5a–n) antiproliferative activity was evaluated against human ER(+) MCF-7 (breast), ER(−) MDA-MB-231 (breast), and Ishikawa (endometrial) cancer cell lines using CellTiter-Glo assay at concentrations ranging from 0.01 to 100,000 nM. Seven compounds showed significant cytotoxicity against at least one cancer cell line with an IC₅₀ value of 25.7–87.8 µM. Compound 5g showed high activity on MCF-7 (IC₅₀ = 25.7 µM), MDA-MB-231 (IC₅₀ = 48.3 µM), and Ishikawa (IC₅₀ = 25.7 µM) cell lines. The newly synthesized molecules were docked in the active sites of the human estrogen receptors (ERs), ER-α (7KBS), and ER-β (2FSZ) crystal structures to determine the locations of the active compounds’ probable binding sites (bioactive conformations).

References

Tran KB, Lang JJ, Compton K, Xu R, Acheson AR, Henrikson HJ, et al. The global burden of cancer attributable to risk factors, 2010–19: A systematic analysis for the global burden of disease study 2019. Lancet. 2022;400(10352):563–91. 10.1016/S0140-6736(22)01438-6.
Open DOI Search in Google Scholar Back to article
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. 10.3322/caac.21660.
Open DOI Search in Google Scholar Back to article
Keri RS, Budagumpi S, Pai RK, Balakrishna RG. Chromones as a privileged scaffold in drug discovery: A review. Eur J Med Chem. 2014;78:340–74. 10.1016/j.ejmech.2014.03.047.
Open DOI Search in Google Scholar Back to article
Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F. Chromone: A valid scaffold in medicinal chemistry. Chem Rev. 2014;114(9):4960–92. 10.1021/cr400265z.
Open DOI Search in Google Scholar Back to article
Gomes LR, Low JN, Cagide F, Gaspar A, Reis J, Borges F. Structural characterization of some N-phenyl-4-oxo-4H-2-chromone carboxamides. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2013;69(Pt 3):294–309. 10.1107/S2052519213009676.
Open DOI Search in Google Scholar Back to article
Shaveta, Singh A, Kaur M, Sharma S, Bhatti R, Singh P. Rational design, synthesis and evaluation of chromone-indole and chromone-pyrazole based conjugates: Identification of a lead for anti-inflammatory drug. Eur J Med Chem. 2014;77:185–92. 10.1016/j.ejmech.2014.03.003.
Open DOI Search in Google Scholar Back to article
Patil VM, Masand N, Verma S, Masand V. Chromones: Privileged scaffold in anticancer drug discovery. Chem Biol Drug Des. 2021;98(5):943–53. 10.1111/cbdd.13951.
Open DOI Search in Google Scholar Back to article
Nam DH, Lee KY, Moon CS, Lee YS. Synthesis and anticancer activity of chromone-based analogs of lavendustin A. Eur J Med Chem. 2010;45(9):4288–92. 10.1016/j.ejmech.2010.06.030.
Open DOI Search in Google Scholar Back to article
Kim SH, Lee YH, Jung SY, Kim HJ, Jin C, Lee YS. Synthesis of chromone carboxamide derivatives with antioxidative and calpain inhibitory properties. Eur J Med Chem. 2011;46(5):1721–8. 10.1016/j.ejmech.2011.02.025.
Open DOI Search in Google Scholar Back to article
Anjum NF, Aleem A, Nayeem N, Asdaq SM. Synthesis and antibacterial activity of substituted 2-phenyl-4-chromones. Der Pharm Chem. 2011;3(5):56–62.
Search in Google Scholar Back to article
Raju BC, Rao RN, Suman P, Yogeeswari P, Sriram D, Shaik TB, et al. Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents. Bioorg Med Chem Lett. 2011;21(10):2855–9. 10.1016/j.bmcl.2011.03.079.
Open DOI Search in Google Scholar Back to article
Kim MK, Yoon H, Barnard DL, Chong Y. Design, synthesis and antiviral activity of 2-(3-amino-4-piperazinylphenyl)chromone derivatives. Chem Pharm Bull (Tokyo). 2013;61(4):486–8. 10.1248/cpb.c12-01050.
Open DOI Search in Google Scholar Back to article
Dengle RV, Deshmukh RN. Synthesis and antimicrobial evaluation of chromones bearing 1, 5-benzo thiazepinyl moiety. Int J Pharml Sci Res. 2013;4:1495–8. 10.13040/IJPSR.0975-8232.4(4).1495-98.
Open DOI Search in Google Scholar Back to article
Gaspar A, Teixeira F, Uriarte E, Milhaze N, Melo A, Cordeiro MN, et al. Towards the discovery of a novel class of monoamine oxidase inhibitors: Structure–Property–Activity and docking studies on chromone amides. Chem Med Chem. 2011;6(4):628–32. 10.1002/cmdc.201000452.
Open DOI Search in Google Scholar Back to article
Reis J, Gaspar A, Milhazes N, Borges F. Chromone as a privileged scaffold in drug discovery: recent advances: Miniperspective. J Med Chem. 2017;60(19):7941–57. 10.1021/acs.jmedchem.6b01720.
Open DOI Search in Google Scholar Back to article
Rao YJ, Abhijit K, Mallikarjun G, Hemasri Y. Design and synthesis of novel benzyloxy-tethered-chromone-carboxamide derivatives as potent and selective human monoamine oxidase-b inhibitors. Chem Pap. 2021;75:703–16. org/10.1007/s11696-020-01332-w.
Open DOI Search in Google Scholar Back to article
Alcaro S, Gaspar A, Ortuso F, Milhazes N, Orallo F, Uriarte E, et al. Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B. Bioorg Med Chem Lett. 2010;20(9):2709–12. 10.1016/j.bmcl.2010.03.081.
Open DOI Search in Google Scholar Back to article
Gaspar A, Reis J, Fonseca A, Milhazes N, Viña D, Uriarte E, et al. Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors. Bioorg Med Chem Lett. 2011;21(2):707–9. 10.1016/j.bmcl.2010.11.128.
Open DOI Search in Google Scholar Back to article
Cagide F, Silva T, Reis J, Gaspar A, Borges F, Gomes LR, et al. Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry. Chem Commun (Camb). 2015;51(14):2832–5. 10.1039/c4cc08798d.
Open DOI Search in Google Scholar Back to article
Cagide F, Gaspar A, Reis J, Chavarria D, Vilar S, Hripcsak G, et al. Navigating in chromone chemical space: discovery of novel and distinct A3 adenosine receptor ligands. RSC Adv. 2015;5:78572–85. 10.1039/C5RA14988F.
Open DOI Search in Google Scholar Back to article
Gaspar A, Reis J, Kachler S, Paoletta S, Uriarte E, Klotz KN, et al. Discovery of novel A3 adenosine receptor ligands based on chromone scaffold. Biochem Pharmacol. 2012;84(1):21–9. 10.1016/j.bcp.2012.03.007.
Open DOI Search in Google Scholar Back to article
Osborne CK, Schiff R, Arpino G, Lee AS, Hilsenbeck VG. Endocrine responsiveness: Understanding how progesterone receptor can be used to select endocrine therapy. Breast. 2005;14(6):458–65. 10.1016/j.breast.2005.08.024.
Open DOI Search in Google Scholar Back to article
Johnston S. Fulvestrant and the sequential endocrine cascade for advanced breast cancer. Br J Cancer. 2004;90(Suppl 1):S15–8. 10.1038/sj.bjc.6601632.
Open DOI Search in Google Scholar Back to article
Jordan VC. The role of Tamoxifen in the treatment and prevention of breast cancer. Curr Probl Cancer. 1992;16(3):129–76. 10.1016/0147-0272(92)90002-6.
Open DOI Search in Google Scholar Back to article
Seema B, Shakti S, Puneet K, Swati K, Manan KD, Akshara S, et al. Synthesis and docking studies on styryl chromones exhibiting cytotoxicity in human breast cancer cell line. Bioorg Med Chem Lett. 2010;20(16):4945–50. org/10.1016/j.bmcl.2010.05.108.
Open DOI Search in Google Scholar Back to article
Ettinger B. Overview of estrogen replacement therapy: a historical perspective. Proc Soc Exp Biol Med. 1998;217(1):2–5. 10.3181/00379727-217-44198.
Open DOI Search in Google Scholar Back to article
Frasor J, Stossi F, Danes JM, Komm B, Lyttle CR, Katzenellenbogen BS. Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res. 2004;64(4):1522–33. 10.1158/0008-5472.can-03-3326.
Open DOI Search in Google Scholar Back to article
Sui M, Huang Y, Park BH, Davidson NE, Fan W. Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death. Cancer Res. 2007;67(11):5337–44. 10.1158/0008-5472.CAN-06-4582.
Open DOI Search in Google Scholar Back to article
Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138(3):863–70. 10.1210/endo.138.3.4979.
Open DOI Search in Google Scholar Back to article
Seeger H, Huober J, Wallwiener D, Mueck AO. Inhibition of human breast cancer cell proliferation with estradiol metabolites is as effective as with Tamoxifen. Horm Metab Res. 2004;36(5):277–80. 10.1055/s-2004-814480.
Open DOI Search in Google Scholar Back to article
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371–88. 10.1093/jnci/90.18.1371.
Open DOI Search in Google Scholar Back to article
Phillips DH, Venitt S. Safety of prophylactic Tamoxifen. Lancet. 1993;341(8858):1485–6. 10.1016/0140-6736(93)90934-9.
Open DOI Search in Google Scholar Back to article
Jordan VC. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205–13. 10.1038/nrd1031.
Open DOI Search in Google Scholar Back to article
Hussain MK, Ansari MI, Yadav N, Gupta PK, Gupta AK, Saxena R, et al. Design and synthesis of ERα/ERβ selective coumarin and chromene derivatives as potential anti-breast cancer and anti-osteoporotic agents. RSC Adv. 2014;4:8828–45. 10.1039/C3RA45749D.
Open DOI Search in Google Scholar Back to article
Saquib M, Baig MH, Khan MF, Azmi S, Khatoon S, Rawat AK, et al. Design and synthesis of bioinspired benzocoumarin-chalcones chimeras as potential anti-breast cancer agents. ChemistrySelect. 2021;6:8754–65. 10.1002/slct.202101853.
Open DOI Search in Google Scholar Back to article
Tong YF, Chen S, Cheng YH, Wu S. A convenient synthesis of 6-demethoxycapillarisin. Chin Chem Lett. 2007;18(4):407–8. 10.1016/j.cclet.2007.01.049.
Open DOI Search in Google Scholar Back to article
Zagorevskii VA, Zykov DA, Orliva EK. Synthesis of Chromone-2-carboxylic Acids and Their Esters. J Gen Chem USSR. 1960;30(12):3850–94.
Search in Google Scholar Back to article
Paulvannan K, Hale R, Mesis R, Chen T. Tandem N-acyliminium/Pictet–Spengler/intramolecular Diels–Alder reaction: an expedient route to hexacyclic tetrahydro-β-carbolines. Tetrahedron Lett. 2002;43(2):203–7. 10.1016/S0040-4039(01)02074-3.
Open DOI Search in Google Scholar Back to article
Lynch JK, Freeman JC, Judd AS, Iyengar R, Mulhern M, Zhao G, et al. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J Med Chem. 2006;49(22):6569–84. 10.1021/jm060683e.
Open DOI Search in Google Scholar Back to article
Crouch SP, Kozlowski R, Slater KJ, Fletcher J. The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. J Immunol Methods. 1993;160:81–8. 10.1016/0022-1759(93)90011-u.
Open DOI Search in Google Scholar Back to article
Gangapuram M, Eyunni S, Redda KK. Synthesis and pharmacological evolution of tetrahydroisoquinolines as anti breast cancer agents. J Cancer Sci Ther. 2014;6:161–9. 10.4172/1948-5956.1000266.
Open DOI Search in Google Scholar Back to article
Suresh VK, Madhavi G, Redda KK. In-vitro antiproliferative activity of new tetrahydroisoquinolines (THIQs) on Ishikawa cells and their 3D pharmacophore models. Lett Drug Des Discov. 2014;11:428–36. 10.2174/1570180811666131203002502.
Open DOI Search in Google Scholar Back to article
Schrödinger Release 2024-1: Maestro. New York, NY: Schrödinger, LLC;s 2024.
Search in Google Scholar Back to article
McCullough C, Neumann TS, Gone JR, He Z, Herrild C, Wondergem Nee Lukesh J, et al. Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study. Bioorg Med Chem. 2014;22(1):303–10. 10.1016/j.bmc.2013.11.024.
Open DOI Search in Google Scholar Back to article

Synthesis, biological evaluation, and molecular docking studies of substituted chromone-2-carboxamide derivatives as anti-breast cancer agents

Abstract

Paradigm

My account