Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin

Md Abdullah Al Noman; David S. Huang; Sara K. Coulup; Shameem Sultana Syeda; Henry L. Wong; Gunda I. Georg

doi:10.1016/j.bioorg.2022.105915

Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin

Md Abdullah Al Noman, David S. Huang, Sara K. Coulup, Shameem Sultana Syeda, Henry L. Wong, Gunda I. Georg

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

2 Scopus citations

Abstract

To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,β-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.

Original language	English (US)
Article number	105915
Journal	Bioorganic Chemistry
Volume	125
DOIs	https://doi.org/10.1016/j.bioorg.2022.105915
State	Published - Aug 2022

Bibliographical note

Funding Information:
The American Foundation for Pharmaceutical Education is acknowledged for a pre-doctoral fellowship (to D.S.H). S. K. C. was supported by a NIH training grant from the National Institute of General Medical Sciences (T32GM008700/T32GM132029) and a NIH Ruth L. Kirschstein National Research Service Award from the National Cancer Institute (NIH/NCI F31CA203039). We also thank Dr. Amy P. N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for OVCAR5. The A2780 cells were provided by the NCI DCTD Tumor repository. Additional funding is acknowledged from the Department of Medicinal Chemistry and the University of Minnesota through the Vince, McKnight, and Regents Endowed Chairs. We would also like to thank Dr. Xianghong Guan for his work on the project. Andrew Goode and Dr. Matthew Cuellar are acknowledged for determining the purity of the final compounds and Dr. C. Leigh Allen for her help with editing of the manuscript.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

Analogs
Antiproliferation
Metabolism
Pironetin
Total synthesis

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin",

abstract = "To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,β-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.",

keywords = "Analogs, Antiproliferation, Metabolism, Pironetin, Total synthesis",

author = "Noman, {Md Abdullah Al} and Huang, {David S.} and Coulup, {Sara K.} and Syeda, {Shameem Sultana} and Wong, {Henry L.} and Georg, {Gunda I.}",

note = "Funding Information: The American Foundation for Pharmaceutical Education is acknowledged for a pre-doctoral fellowship (to D.S.H). S. K. C. was supported by a NIH training grant from the National Institute of General Medical Sciences (T32GM008700/T32GM132029) and a NIH Ruth L. Kirschstein National Research Service Award from the National Cancer Institute (NIH/NCI F31CA203039). We also thank Dr. Amy P. N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for OVCAR5. The A2780 cells were provided by the NCI DCTD Tumor repository. Additional funding is acknowledged from the Department of Medicinal Chemistry and the University of Minnesota through the Vince, McKnight, and Regents Endowed Chairs. We would also like to thank Dr. Xianghong Guan for his work on the project. Andrew Goode and Dr. Matthew Cuellar are acknowledged for determining the purity of the final compounds and Dr. C. Leigh Allen for her help with editing of the manuscript. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = aug,

doi = "10.1016/j.bioorg.2022.105915",

language = "English (US)",

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T1 - Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin

AU - Noman, Md Abdullah Al

AU - Huang, David S.

AU - Coulup, Sara K.

AU - Syeda, Shameem Sultana

AU - Wong, Henry L.

AU - Georg, Gunda I.

N1 - Funding Information: The American Foundation for Pharmaceutical Education is acknowledged for a pre-doctoral fellowship (to D.S.H). S. K. C. was supported by a NIH training grant from the National Institute of General Medical Sciences (T32GM008700/T32GM132029) and a NIH Ruth L. Kirschstein National Research Service Award from the National Cancer Institute (NIH/NCI F31CA203039). We also thank Dr. Amy P. N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for OVCAR5. The A2780 cells were provided by the NCI DCTD Tumor repository. Additional funding is acknowledged from the Department of Medicinal Chemistry and the University of Minnesota through the Vince, McKnight, and Regents Endowed Chairs. We would also like to thank Dr. Xianghong Guan for his work on the project. Andrew Goode and Dr. Matthew Cuellar are acknowledged for determining the purity of the final compounds and Dr. C. Leigh Allen for her help with editing of the manuscript. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/8

Y1 - 2022/8

N2 - To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,β-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.

AB - To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,β-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.

KW - Analogs

KW - Antiproliferation

KW - Metabolism

KW - Pironetin

KW - Total synthesis

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DO - 10.1016/j.bioorg.2022.105915

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SN - 0045-2068

VL - 125

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 105915

ER -

Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin

Abstract

Bibliographical note

Keywords

UN SDGs

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