Abstract
In recent years, focusing on new potent anticancer agents with selective activity is one of the greatest challenges in cancer therapy. Breast cancer is the most common cancer and the main cause of cancer deaths in women. The sulfatase enzyme plays an important role in converting the sulfated steroids into non-sulfate steroid hormones, which increases the growth and development of many hormone-dependent cancers, such as breast cancer. In this regard, structure-based optimization was conducted to design novel flavone-sulfonates pharmacophore as a new steroid sulfatase inhibitor. In the present work, the conventional methods for the synthesis of 4-oxo-2-phenyl-4H-chromen-7-yl methanesulfonate derivatives were reported. Their cytotoxicity was evaluated with MTT assay against a breast cancer cell line (MCF-7). The apoptosis inducing activity of the most cytotoxic compound 3c with an IC50 value of 0.615 µM was evaluated in comparison to docetaxel in the presence of estradiol which is a crucial growth factor to survive the cancerous cells. The results of double staining Annexin V-FITC/PI analysis suggested that the cytotoxic activity of this compound 3c in MCF-7 cells occurs via apoptosis. Molecular docking studies were conducted to clarify the inhibition mode of the most promising compound (3c) over the sulfatase (1P49) binding site. The analysis revealed the role of hydrogen bond interaction with Gly181 and hydrophobic interactions through the 1P49 active site in the ligand-receptor complex as significant descriptors to rationalize the potential inhibition activity.
Highlights
Cancer is known as a chronic and non-communicable disease [1]
The first steroidal STS inhibitors were designed based on the similarity with the substrate parental structure. Hallmark in this regard back to 1994 in which the replacement of OH of the sulfate group (A, Fig. 1) by an NH2, generated estrone-3-O-sulfamate known as EMATE (C, Fig. 1,) as an irreversible steroidal inhibitor. This compound performed a great activity in MCF-7 cells, with an IC50 value of 65 pM [13]
High estrogenicity was observed with estrogenic inhibitors and unsuitable effects were seen as anticancer agents
Summary
Cancer is known as a chronic and non-communicable disease [1]. In more than a hundred different kinds of cancers, breast cancer is the most common cancer and the main cause of cancer deaths in women [2]. The World Health Organization (WHO) reports biologically active hormones, including estrogens, as one of the most important factors to develop breast cancer. Steroid sulfatase (STS) is known as a sulfatase enzyme that catalyzes the conversion of sulfated steroid (hormone precursors) to free steroid (active form) that stimulates the growth of tumors in various tissues especially the breast. Some STS inhibitors have entered clinical trials and their efficacy is under investigation in postmenopausal women with breast cancer [10, 11]. Inhibition of this enzyme decreases the level of the active hormone, which responsible strategy to target the breast, endometrial, prostate, and other hormone-sensitive cancers [12]
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