| Summary: | Skin cancers are a dominant type of cancer that impacts millions per year. Cancer is a heterogeneous disease triggered by the irreversible impairment of cellular homeostasis and function. In this study, we investigated the activity of 37 structurally diverse flavonoids to find potentially active substances using two melanoma cell lines: C32 and A375. First, the cytotoxic potential and DNA biosynthesis inhibition of flavonoids were tested to determine the most active compounds in cancer and normal cells. Second, the molecular mechanism of the anticancer activity of flavonoids was elucidated using Western blot and immunofluorescence analyses. Compounds <b>1</b>, <b>6</b>, <b>15</b>, and <b>37</b> reduced the viability of A375 and C32 cell lines via the intrinsic and extrinsic pathways of apoptosis, whereas <b>16</b> and <b>17</b> acted in a higher degree via the inhibition of DNA biosynthesis. In our experiment, we demonstrated the anticancer activity of compound <b>15</b> (5,6-dihydroxyflavone) for the first time. The in vitro studies pointed out the importance of the flavonoid core in hydroxyl groups in the search for potential drugs for amelanotic melanoma.
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