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>