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

doi:10.1016/j.bmcl.2012.07.050

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

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

7 Scopus citations

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 language	English (US)
Pages (from-to)	5961-5965
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2012.07.050
State	Published - Sep 15 2012

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

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmcl.2012.07.050

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

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.",

author = "Kim, \{Young B.\} and Balasis, \{Maria E.\} and Kenichiro Doi and Norbert Berndt and Courtney Duboulay and Hu, \{Chih Chi Andrew\} and Wayne Guida and Wang, \{Hong Gang\} and Sebti, \{Sa{\"i}d M.\} and \{Del Valle\}, \{Juan R.\}",

note = "Funding Information: This research was supported by the James and Esther King Biomedical Research Program, Florida Department of Health (Grant 1BN03 to JRD) and the National Institutes of Health (Grant P01CA118210 to SMS). ",

year = "2012",

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day = "15",

doi = "10.1016/j.bmcl.2012.07.050",

language = "English (US)",

volume = "22",

pages = "5961--5965",

journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction

AU - Kim, Young B.

AU - Balasis, Maria E.

AU - Doi, Kenichiro

AU - Berndt, Norbert

AU - Duboulay, Courtney

AU - Hu, Chih Chi Andrew

AU - Guida, Wayne

AU - Wang, Hong Gang

AU - Sebti, Saïd M.

AU - Del Valle, Juan R.

N1 - Funding Information: This research was supported by the James and Esther King Biomedical Research Program, Florida Department of Health (Grant 1BN03 to JRD) and the National Institutes of Health (Grant P01CA118210 to SMS).

PY - 2012/9/15

Y1 - 2012/9/15

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84865527025

UR - https://www.scopus.com/pages/publications/84865527025#tab=citedBy

U2 - 10.1016/j.bmcl.2012.07.050

DO - 10.1016/j.bmcl.2012.07.050

M3 - Article

C2 - 22901384

AN - SCOPUS:84865527025

SN - 0960-894X

VL - 22

SP - 5961

EP - 5965

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

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

Abstract

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