Design and combinatorial synthesis of N-acyl iminodiacetic acids as bongkrekic acid analogues for the inhibition of adenine nucleotide translocase

The adenine nucleotide translocase (ANT) mediates ADP/ATP exchange in mitochondria and is also a critical component of the mitochondrial permeability transition (MPT) pore. Opening of this physiological pore has been implicated as a key step in initiating cell death, hence agents that prevent MPT pore opening may be of potential therapeutic value. The natural product bongkrekic acid is a potent ANT inhibitor that is reported to block MPT opening. We present the design and synthesis of N-acyl iminodiacetic acids as novel inhibitors of ANT-1, using bongkrekic acid as an initial lead. The identification of potent ANT-1 inhibitors from a primary binding assay and the preliminary structure-activity relationship based on these new leads are discussed.