Over-expression of the anti-apoptotic Bcl-2 proteins, such as Mcl-1 and Bcl-xL, is associated with the development and progression of a variety of cancers. Through the �neutralization� of the amphipathic, a-helical BH3 �death� domains of pro-apoptotic Bcl-2 proteins, such as Bak and Bim, the anti-apoptotic Bcl-2 proteins inhibit cell death. Towards the dual inhibition of Mcl-1 and Bcl-xL, we have rationally designed amphipathic a-helix mimetics of the BH3 a-helix based on a 2,6,9-tri-substituted purine scaffold. Starting from N2-Boc-2-amino-6-chloropurine, two sequential Mitsunobu reactions at the N9 and N2 positions installed mimetics of the side-chains of Phe69 and Ile65, respectively, of the Bim-BH3 helix, which, along with the N2-Boc group as a mimetic of Leu62, completed construction of the hydrophobic face. Finally, displacement of the 6-chloro group employing SNAr chemistry introduced mimetics of Asp67 on the hydrophilic face of the purine-based a-helix mimetic. Preliminary studies indicate our compounds function as pan-Bcl-2 inhibitors.

2,6,9-Tri-substituted purines as amphipathic a-helix mimetics to inhibit the anti-apoptotic Bcl-2 proteins

247th National Meeting (2014)

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