Abstract

Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40 μM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.

Original languageEnglish
Pages (from-to)5528-5533
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number22
DOIs
Publication statusPublished - 2016

Fingerprint

Lovastatin
Reactive Oxygen Species
Cytotoxicity
Cells
Cell death
Metabolites
Fungi
Cisplatin
Hypercholesterolemia
Apoptosis
DNA Damage
Neoplasms
Prostatic Neoplasms
Cell Cycle
Cell Death
DNA
Cell Line

Keywords

  • Aliphatic hydroxamate
  • Fungus metabolite
  • Lovastatin
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species. / Lin, Ruo Kai; Lin, Yuh Feng; Hsu, Ming Jen; Hsieh, Chang Lin; Wang, Chen Yu; Huang, Chih Chiang; Huang, Wei Jan.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 22, 2016, p. 5528-5533.

Research output: Contribution to journalArticle

@article{9bd575383c8a48cb81c191952063b548,
title = "Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species",
abstract = "Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40 μM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.",
keywords = "Aliphatic hydroxamate, Fungus metabolite, Lovastatin, Reactive oxygen species",
author = "Lin, {Ruo Kai} and Lin, {Yuh Feng} and Hsu, {Ming Jen} and Hsieh, {Chang Lin} and Wang, {Chen Yu} and Huang, {Chih Chiang} and Huang, {Wei Jan}",
year = "2016",
doi = "10.1016/j.bmcl.2016.10.005",
language = "English",
volume = "26",
pages = "5528--5533",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Ireland Ltd",
number = "22",

}

TY - JOUR

T1 - Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species

AU - Lin, Ruo Kai

AU - Lin, Yuh Feng

AU - Hsu, Ming Jen

AU - Hsieh, Chang Lin

AU - Wang, Chen Yu

AU - Huang, Chih Chiang

AU - Huang, Wei Jan

PY - 2016

Y1 - 2016

N2 - Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40 μM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.

AB - Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40 μM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.

KW - Aliphatic hydroxamate

KW - Fungus metabolite

KW - Lovastatin

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=84994013630&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994013630&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.10.005

DO - 10.1016/j.bmcl.2016.10.005

M3 - Article

C2 - 27756564

AN - SCOPUS:84994013630

VL - 26

SP - 5528

EP - 5533

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 22

ER -