Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues

Aaron M. Kempema; John C. Widen; Joseph K. Hexum; Timothy E. Andrews; Dan Wang; Susan K. Rathe; Frederick A. Meece; Klara E. Noble; Zohar Sachs; David A. Largaespada; Daniel A. Harki

doi:10.1016/j.bmc.2015.05.037

Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues

Aaron M. Kempema, John C. Widen, Joseph K. Hexum, Timothy E. Andrews, Dan Wang, Susan K. Rathe, Frederick A. Meece, Klara E. Noble, Zohar Sachs, David A. Largaespada, Daniel A. Harki

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4737-4745
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2015.05.037
State	Published - Jul 23 2015

Bibliographical note

Funding Information:
We thank Ezra Menon and Margaret Olson (University of Minnesota, UMN) for assistance with anti-proliferative activity experiments and Victor G. Young, Jr. of the Department of Chemistry, X-ray Crystallographic Laboratory (UMN) for solving the X-ray structures of 1 , 3 , and 4 . We thank Professor Michael Verneris (UMN) for assistance with flow cytometry analysis and NIH P30 CA77598, which supports the Flow Cytometry shared resource of the Masonic Cancer Center (UMN). Professor John Dick (University of Toronto) is gratefully acknowledged for the gift of the TEX cell line. GBM6 cells were a gift from the late Professor John Ohlfest (UMN). This research was supported by grants from the UMN , Academic Health Center (Seed Grant 2010.01 ); UMN, Leukemia Research Fund—Danny Thompson Memorial Golf Tournament ; Children’s Cancer Research Fund, Minneapolis , MN; American Cancer Society ( IRG-58-001-52-IRG68 ); Hyundai Hope on Wheels, Hope Grant Award ; The V Foundation for Cancer Research , V Scholar Award to D.A.H.; and startup funds to D.A.H. from the UMN. J.C.W. thanks the UMN, College of Pharmacy for a Bighley Graduate Fellowship. D.W. acknowledges the American Heart Association for a predoctoral fellowship (11PRE7240035).

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

Acute myeloid leukemia
Bone marrow toxicity
Cyclopropanation
Parthenolide
Sesquiterpene lactone

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title = "Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues",

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.",

keywords = "Acute myeloid leukemia, Bone marrow toxicity, Cyclopropanation, Parthenolide, Sesquiterpene lactone",

author = "Kempema, {Aaron M.} and Widen, {John C.} and Hexum, {Joseph K.} and Andrews, {Timothy E.} and Dan Wang and Rathe, {Susan K.} and Meece, {Frederick A.} and Noble, {Klara E.} and Zohar Sachs and Largaespada, {David A.} and Harki, {Daniel A.}",

note = "Funding Information: We thank Ezra Menon and Margaret Olson (University of Minnesota, UMN) for assistance with anti-proliferative activity experiments and Victor G. Young, Jr. of the Department of Chemistry, X-ray Crystallographic Laboratory (UMN) for solving the X-ray structures of 1 , 3 , and 4 . We thank Professor Michael Verneris (UMN) for assistance with flow cytometry analysis and NIH P30 CA77598, which supports the Flow Cytometry shared resource of the Masonic Cancer Center (UMN). Professor John Dick (University of Toronto) is gratefully acknowledged for the gift of the TEX cell line. GBM6 cells were a gift from the late Professor John Ohlfest (UMN). This research was supported by grants from the UMN , Academic Health Center (Seed Grant 2010.01 ); UMN, Leukemia Research Fund—Danny Thompson Memorial Golf Tournament ; Children{\textquoteright}s Cancer Research Fund, Minneapolis , MN; American Cancer Society ( IRG-58-001-52-IRG68 ); Hyundai Hope on Wheels, Hope Grant Award ; The V Foundation for Cancer Research , V Scholar Award to D.A.H.; and startup funds to D.A.H. from the UMN. J.C.W. thanks the UMN, College of Pharmacy for a Bighley Graduate Fellowship. D.W. acknowledges the American Heart Association for a predoctoral fellowship (11PRE7240035). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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AU - Widen, John C.

AU - Hexum, Joseph K.

AU - Andrews, Timothy E.

AU - Wang, Dan

AU - Rathe, Susan K.

AU - Meece, Frederick A.

AU - Noble, Klara E.

AU - Sachs, Zohar

AU - Largaespada, David A.

AU - Harki, Daniel A.

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N2 - 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.

AB - 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.

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KW - Bone marrow toxicity

KW - Cyclopropanation

KW - Parthenolide

KW - Sesquiterpene lactone

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Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues

Abstract

Bibliographical note

Keywords

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