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

• Published in: Natural product research Vol. 32; no. 2; pp. 128 - 132
• Main Authors: Zhang, Xinxin, Li, Dandan, Xue, Xuanji, Zhang, Yan, Zhang, Jie, Huang, Chen, Guo, Zengjun, Tadesse, Nigatu
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2018; Taylor & Francis Ltd
• Subjects: Aconitum; Aconitum - chemistry; Aconitum taipeicum; Alkaloids - chemical synthesis; Alkaloids - pharmacology; Amides - chemical synthesis; Amides - pharmacology; anticancer; Anticancer properties; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Cancer; Caspase; Caspase 3 - metabolism; Caspase-3; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cytometry; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Flow cytometry; Humans; Intermediates; ITPD; Mitochondria; Mitochondria - metabolism; S phase; Synthesis; Total synthesis; apoptosis; ITPD; Aconitum taipeicum; Total synthesis; anticancer
• ISSN: 1478-6419; 1478-6427
• DOI: 10.1080/14786419.2017.1340283

A concise total synthesis of a naturally occurring 3-isopropyl-tetrahydropyrrolo[1, 2-a]pyrimidine-2, 4(1H, 3H)-dione (ITPD) isolated from Aconitum taipeicum with a three-step approach was depicted in this study for the first time. Two key intermediates, diethyl isopropylmalonate (2) and pyrrolidin-2-amine (3), being synthsesised separately from initial diethyl malonate (4) and 3, 4-dihydro-2H-pyrrol-5-amine (5), were utilised to obtain the compound entitled ITPD. ITPD showed a promising anticancer activity in vitro 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 in vivo and in vitro. The bioactive assay suggested that it may be a potential candidate for further chemical optimisation and use in cancer therapy.