Abstract
Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC50 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC50 values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.
Highlights
Breast cancer is the most prevalent malignancy in females and the second most common cause of death in women after lung cancer [1]
Triple negative breast cancer (TNBC) is resistant to current hormone-based chemotherapies or anti-HER2 treatments [5,6], there is still an urgent need to search for a new molecular targets and therapeutic approaches that would be effective in TNBC treatment [7,8]
The acylation of alcohols is one of the most convenient methods to protect their hydroxyl groups [48]. In medicinal chemistry, such simple functionalization of small molecules is often utilized to obtain prodrugs with markedly affected pharmaco-kinetic properties when compared to the parent underivatized active pharmaceutical ingredients (APIs) [49,50,51]
Summary
Breast cancer is the most prevalent malignancy in females and the second most common cause of death in women after lung cancer [1]. Protein kinase CK2 (formerly known as casein kinase II) is an enzyme that catalyzes phosphorylation of a huge number of substrates, and is involved in the regulation of many processes such as transcription [9,10], translation [11,12,13,14], control of protein stability [15,16,17] and degradation [18,19], cell cycle progression [20], cell survival [21,22,23] as well as circadian rhythms [24] The role of this conserved constitutively active serine-threonine kinase in the cell regulatory network is highly complex, and the extensive interplay between CK2-mediated phosphorylation and other post-translational modifications has been suggested [25]. An increased level/activity of CK2 kinase has been observed in several tumor types [29], including breast cancer, where overexpression of CK2 results in the dysregulation of key cellular signalling pathways that control transcription factors of mammary epithelium [30]
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