Alkyne–azide cycloaddition analogues of dehydrozingerone as potential anti-prostate cancer inhibitors <i>via</i> the PI3K/Akt/NF-kB pathway

Abstract

Herein, we report the isolation and synthetic modification of dehydrozingerone (DHZ, <b>1</b>), a secondary metabolite present in the rhizome of <i>Zingiber officinale</i>. We synthesized <i>O</i>-propargylated dehydrozingerone, which was subsequently coupled by alkyne-azide cycloaddition (<b>3-20</b>) using click chemistry. The compounds (<b>1-20</b>) were evaluated for their <i>in vitro</i> cytotoxic activity in a panel of three cancer cell lines. Among all the DHZ derivatives, <b>3</b>, <b>6</b>, <b>7</b>, <b>8</b>, <b>9</b> and <b>15</b> displayed potent cytotoxic potential with an IC₅₀ value ranging from 1.8-3.0 μM in MCF-7, PC-3 and HCT-116 cell lines. Furthermore, compound <b>7</b> has proven to be the most potent cytotoxic compound in all the three distinct cancer cell lines and also demonstrated significant anti-invasive potential in prostate cancer. The mechanistic study of compound <b>7</b> showed that it not only suppressed the AKT/mTOR signalling which regulates nuclear transcription factor-NF-kB but also augmented the expression of anti-invasive markers E-cadherin and TIMP. Compound <b>7</b> significantly decreased the expression of pro-invasive markers vimentin, MMP-2 and MMP-9, respectively. This study underscores an efficient synthetic approach employed to evaluate the structure-activity relationship of dehydrozingerone (<b>1</b>) in search of potential new anticancer agents.