10.6084/m9.figshare.7082597.v1 Yahui Ding Yahui Ding Zhongjin Yang Zhongjin Yang Weizhi Ge Weizhi Ge Beijia Kuang Beijia Kuang Junqing Xu Junqing Xu Juan Yang Juan Yang Yue Chen Yue Chen Quan Zhang Quan Zhang Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents Taylor & Francis Group 2018 Parthenolide dithiocarbamate leukaemia stem cell MAPK pathway synthesis 2018-09-13 08:03:52 Journal contribution https://tandf.figshare.com/articles/journal_contribution/Synthesis_and_biological_evaluation_of_dithiocarbamate_esters_of_parthenolide_as_potential_anti-acute_myelogenous_leukaemia_agents/7082597 <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>