Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer

Abstract

Background: : Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman’s risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. Objective:: In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. Methods: : A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. Results: Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25μg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. Conclusion:: Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment

“…Because labelled U0126 competes with PD98059 for MEK1 binding, they appear to bind to the same sites on the protein. 62 While it has been demonstrated that U0126 and PD98059 suppress MEK1 phosphorylation and ERK1 and ERK2 activation, these first-generation MEK inhibitors have been extensively used in vivo to identify ERK1 and ERK2 biological activity. Moreover, these two inhibitors have recently been demonstrated to limit ERK5 pathway activation via direct actions on MEK5.…”

Targeting Solid Tumors With BTK Inhibitors

“…Coumarins are derivatives of 2H-1-benzopyran-2-one, which naturally occurs in plants as free coumarins or their glycoside derivatives (Kashman et al, 1992;Currens et al, 1996;McKee et al, 1998;Creagh et al, 2001;Shokoohinia et al, 2018;Bhatia and Rawal, 2019;Kawai et al, 2019;Li et al, 2019;Lin et al, 2019;Makowska et al, 2019;Ramdani et al, 2019;Selvaraj et al, 2019;Wang et al, 2019;Zhang and Xu, 2019). Coumarins have been known for their proapoptotic anticancer activity with inhibitory effects on tumor-promoting signal transduction pathways as well as antiviral activity (Kashman et al, 1992;Currens et al, 1996;McKee et al, 1998;Creagh et al, 2001;Shokoohinia et al, 2018;Bhatia and Rawal, 2019;Kawai et al, 2019;Li et al, 2019;Lin et al, 2019;Makowska et al, 2019;Ramdani et al, 2019;Selvaraj et al, 2019;Wang et al, 2019;Zhang and Xu, 2019). The naturally occurring coumarin derivatives, (+)-calanolide A and (-)-calanolide B, have been identified as inhibitors of non-nucleoside HIV-1-specific reverse-transcriptase inhibitory activity (Kashman et al, 1992;Currens et al, 1996;Creagh et al, 2001).…”

“…Several semi-synthetic calanolide derivatives have been developed as antiviral drug candidates (Creagh et al, 2001;Sagiv-Barfi et al, 2015;Chen et al, 2016). Researchers have hybridized coumarin moieties with other anticancer pharmacophores as a strategy of developing novel anticancer drugs (Flavin et al, 1996;Bhatia and Rawal, 2019;Kawai et al, 2019;Lin et al, 2019;Makowska et al, 2019;Ramdani et al, 2019;Selvaraj et al, 2019;Wang et al, 2019;Zhang and Xu, 2019). In addition, some natural coumarins such as Psoralidin (Li et al, 2019) and Osthol (Shokoohinia et al, 2018) have been reported to exhibit potent in vitro and in vivo anticancer activity.…”

“…In addition, some natural coumarins such as Psoralidin (Li et al, 2019) and Osthol (Shokoohinia et al, 2018) have been reported to exhibit potent in vitro and in vivo anticancer activity. Coumarinfatty acid conjugates as well as coumarin hybrids generated via coupling with isoxazole, thiazole, monastrol, chalcone, triazole, sulfonamide, triphenylethylene, benzimidazole, pyran, imidazole, stilbene, estrogen, or phenylsulfonylfuroxan exhibited promising pro-apoptotic anticancer activity (Bhatia and Rawal, 2019;Kawai et al, 2019;Makowska et al, 2019;Selvaraj et al, 2019;Zhang and Xu, 2019).…”

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

“…The estrogen dependency of breast cancer represents a unique feature of the disease that can be manipulated to effectively control growth and/or prevent tumor development. Indeed, the current strategy for treatment of hormone-dependent breast cancer is to block the action of estrogen on tumor cells through either of three possibilities: (a) inhibiting estrogen from binding to its main target ERα using an antiestrogen such as tamoxifen/raloxifen [3][4][5][6][7][8] ; (b) preventing estrogen synthesis using an aromatase inhibitor [9][10][11][12][13][14][15] ; (c) down-regulating ERα protein levels using a pure antiestrogen such as fulvestrant [16][17] .…”