Synthesis and antileukemic activities of C1–C10-modified parthenolide analogues. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Kempema, Aaron M.; Widen, John C.; Hexum, Joseph K.; Andrews, Timothy E.; Wang, Dan; Rathe, Susan K.; Meece, Frederick A.; Noble, Klara E.; Sachs, Zohar; Largaespada, David A.; Harki, Daniel A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 4737
• Page End: 4745
• Publication Date: 2015-08-01
• Subjects: PTL parthenolide -- LSC leukemic stem cell -- AML acute myeloid leukemia -- SL sesquiterpene lactone -- HSC hematopoietic stem cell -- DMAPT dimethylamino-parthenolide -- MelB melampomagnolide B -- ROS reactive oxygen species -- PtO2 platinum(IV) oxide -- DME dimethoxyethane -- Log D distribution coefficient -- CSC cancer stem cell -- CTL costunolide -- BM bone marrow -- DOX doxorubicin -- AraC cytarabine -- MEM minimum essential medium -- FBS fetal bovine serum -- DMEM Dulbecco's modified Eagle medium -- HEPES (4-2-hydroxyethyl)-1-piperazineethanesulfonic acid) -- IMDM Iscove's modified Dulbecco's medium -- MTS 3-(4, 5-dimethylthiaol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium -- SFEM serum-free expansion medium; Bone marrow toxicity -- Cyclopropanation -- Acute myeloid leukemia -- Parthenolide -- Sesquiterpene lactone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.05.037
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Parthenolide (PTL ) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1–C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL .