First total synthesis of a novel amide alkaloid derived from <i>Aconitum taipeicum</i> and its anticancer activity

<p>A concise total synthesis of a naturally occurring 3-isopropyl-tetrahydropyrrolo[1, 2-a]pyrimidine-2, 4(1H, 3H)-dione (ITPD) isolated from <i>Aconitum taipeicum</i> with a three-step approach was depicted in this study for the first time. Two key intermediates, diethyl isopropylmalonate (<b>2</b>) and pyrrolidin-2-amine (<b>3</b>), being synthsesised separately from initial diethyl malonate (<b>4</b>) and 3, 4-dihydro-2H-pyrrol-5-amine (<b>5</b>), were utilised to obtain the compound entitled ITPD. ITPD showed a promising anticancer activity <i>in vitro</i> on SMMC-7721 cell lines. Flow cytometry and cell cycle analysis revealed that ITPD could induce apoptosis and cell cycle arrest in S phase. The occurrence of apoptosis possibly attributed to the mechanism that ITPD could mediate the mitochondrial pathway through activating caspase-3/9 and increasing the ratio of Bax/Bcl-2 to finally trigger cell apoptosis and DNA damage. Collectively, the possibility to produce sufficient quantity of synthetic ITPD provided the base for further bio-evaluation <i>in vivo</i> and <i>in vitro</i>. The bioactive assay suggested that it may be a potential candidate for further chemical optimisation and use in cancer therapy.</p>