| Summary: | Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (<b>PQs</b>) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of <b>PQ</b> analogs. Among these analogs, <b>PQ2</b>, <b>PQ3</b> and <b>PQ10</b> were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of <b>PQ2</b> on the HCT-116 colorectal cancer cell line than that of <b>PQ3</b> and <b>PQ10</b> compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of <b>PQ2</b>. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for <b>PQ2</b> at different concentrations against HCT-116 cells. Results indicated that <b>PQ2</b> exhibited significant cytotoxicity in HCT-116 cells with an IC<sub>50</sub> value of 4.97 ± 1.93 μM compared to cisplatin (IC<sub>50</sub> = 26.65 ± 7.85 μM). Moreover, apoptotic effects of <b>PQ2</b> on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and <b>PQ2</b> significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of <b>PQ2</b>, molecular docking studies were conducted in the minor groove of the double helix of DNA and <b>PQ2</b> presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like <b>PQ2</b> attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.
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