Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction

Young B. Kim, Maria E. Balasis, Kenichiro Doi, Norbert Berndt, Courtney Duboulay, Chih Chi Andrew Hu, Wayne Guida, Hong Gang Wang, Saïd M. Sebti, Juan R. Del Valle

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Abstract

Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in a broad range of human cancers and plays a critical role in conferring resistance to chemotherapy. In the course of screening a natural product-like library of sesquiterpenoid analogs, we identified substituted hexahydronaphthalenes that showed activity against the Mcl-1/BimBH3 interaction in vitro. Here, we describe the synthesis of a small library of analogs and their biological evaluation. The most potent inhibitor in the series (19) exhibits an IC50 of 8.3 μM by ELISA and disrupts the interaction between endogenously expressed Mcl-1 and Bim in cultured MDA-MB-468 breast cancer cells.

Original languageEnglish (US)
Pages (from-to)5961-5965
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2012

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All Science Journal Classification (ASJC) codes

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

Cite this

Kim, Y. B., Balasis, M. E., Doi, K., Berndt, N., Duboulay, C., Hu, C. C. A., Guida, W., Wang, H. G., Sebti, S. M., & Del Valle, J. R. (2012). Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction. Bioorganic and Medicinal Chemistry Letters, 22(18), 5961-5965. https://doi.org/10.1016/j.bmcl.2012.07.050