Abstract
We designed and synthesized the 1,3,4-thiadiazole derivatives differing in the structure of the substituents in C2 and C5 positions. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and normal cell line (fibroblasts). The results showed that in both breast cancer cell lines, the strongest anti-proliferative activity was exerted by 2-(2-trifluorometylophenylamino)-5-(3-methoxyphenyl)-1,3,4-thiadiazole. The IC50 values of this compound against MCF-7 and MDA-MB-231 breast cancer cells were 49.6 µM and 53.4 µM, respectively. Importantly, all new compounds had weaker cytotoxic activity on normal cell line than on breast cancer cell lines. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds. The most likely mechanism of action for the new compounds is connected with the activities of Caspase 3 and Caspase 8 and activation of BAX proteins.
Highlights
Breast cancer affects 14% of all women living in the world [1]
Estrogens are listed by the WHO as one of the most important factors stimulating the development of breast cancer
The cytotoxic activity of the obtained compounds was determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells
Summary
Breast cancer affects 14% of all women living in the world [1]. It is the most frequently diagnosed neoplasm in female patients. One of the main problems of the pharmacotherapy of cancers, including breast cancer, is the rapidly developing drug resistance. For this reason, it is necessary to search for new anticancer drugs [2]. Estrogens are listed by the WHO as one of the most important factors stimulating the development of breast cancer. Many of the pharmacological treatments for breast cancer currently available, such as tamoxifen, mainly target the estrogen receptors (ER). As a consequence, these drugs are not effective in the treatment of non-estrogen-dependent cases of breast cancer. Research is ongoing to find new therapeutic and chemopreventive agents acting independently of estrogen receptors, effective against both estrogen-dependent and non-estrogen-dependent breast cancer cells [3]
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