Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents

<p>A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound <b>7l</b> showed greatly improved potency against AML progenitor cell line KG1a with IC<sub>50</sub> value of 0.7 μM, and the efficacy was 8.7-folds comparing to that of PTL (IC<sub>50</sub> = 6.1 μM). Compound <b>7l</b> induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells. Furthermore, <b>7l</b> suppressed the colony formation of primary human leukaemia cells. Moreover, compound <b>12</b>, the salt form of <b>7l</b>, prolonged the lifespan of mice in two patient-derived xenograft models and had no observable toxicity. The preliminary molecular mechanism study revealed that <b>7l</b>-mediated apoptosis is associated with mitogen-activated protein kinase signal pathway. On the basis of these investigations, we propose that <b>12</b> might be a promising drug candidate for ultimate discovery of anti-LSCs drug.</p>