Novel synthetic chalcones induce apoptosis in the A549 non-small cell lung cancer cells harboring a KRAS mutation

Yiqiang Wang; Andreas Hedblom; Steffi K Koerner; Mailin Li; Finith E Jernigan; Barbara Wegiel; Lijun Sun

doi:10.1016/j.bmcl.2016.10.063

Novel synthetic chalcones induce apoptosis in the A549 non-small cell lung cancer cells harboring a KRAS mutation

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5703-5706. doi: 10.1016/j.bmcl.2016.10.063. Epub 2016 Oct 24.

Authors

Yiqiang Wang¹, Andreas Hedblom², Steffi K Koerner¹, Mailin Li², Finith E Jernigan¹, Barbara Wegiel³, Lijun Sun⁴

Affiliations

¹ Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² Transplant Institute & Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
³ Transplant Institute & Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
⁴ Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].

Abstract

A series of novel chalcones were synthesized by the Claisen-Schmidt condensation reaction of tetralones and 5-/6-indolecarboxaldehydes. Treatment of human lung cancer cell line harboring KRAS mutation (A549) with the chalcones induced dose-dependent apoptosis. Cell cycle analyses and Western blotting suggested the critical role of the chalcones in interrupting G2/M transition of cell cycle. SAR study demonstrated that substituent on the indole N atom significantly affects the anticancer activity of the chalcones, with methyl and ethyl providing the more active compounds (EC₅₀: 110-200nM), Compound 1g was found to be >4-fold more active in the A549 cells (EC₅₀: 110nM) than in prostate (PC3) or pancreatic cancer (CLR2119, PAN02) cells. Furthermore, compound 1l selectively induced apoptosis of lung cancer cells A549 (EC₅₀: 0.55μM) but did not show measurable toxicity in the normal lung bronchial epithelial cells (hBEC) at doses as high as 10μM, indicating specificity towards cancer cells.

Keywords: Apoptosis; Cell cycle; Chalcone; KRAS; Non-small cell lung cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / pharmacology*
Humans
Lung / drug effects
Lung / metabolism
Lung / pathology
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mutation
Proto-Oncogene Proteins p21(ras) / genetics*

Substances

Antineoplastic Agents
Chalcones
KRAS protein, human
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding