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 IC(50) 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.

Figure 1

Structure of hexahydronaphthanlene 1 and analogs.

Figure 2

ELISA Mcl-1/BimBH3 dose-response curves for 10, 19, and 23 (95% confidence intervals in parentheses).

Figure 3

Co-immunoprecipitation of Mcl-1 (with Bim) from MDA-MB-468 cells. (A) Samples compared in the same gel for each protein and (B) densitometric analysis of inhibition.

Figure 4

Top-scoring poses for (A) (1R,4aS,6R,8aS)-19 and (B) (1S,4aR,6S,8aR)-19 docked to human Mcl-1 (PDB code 2NL9) using GLIDE.

Scheme 1

Synthesis of hexahydronaphthalene scaffold 5.

Scheme 2

Analog synthesis.