Design and Combinatorial Synthesisof N-Acyl Iminodiacetic Acids as BongkrekicAcid Analogues for the Inhibition of Adenine Nucleotide Translocase

Abstract

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.Adenine nucleotide translocase (ANT) is an abundant integral mitochondrial inner membrane protein, whose key function is the selective exchange of cytosolic ADP for mitochondrial matrix ATP across the otherwise impermeable inner mitochondrial membrane. By providing the mitochondrial oxidative phosphorylation machinery with substrate for ATP production, and by supplying the cell with a high-energy phosphate source, the ANT-facilitated exchange of ADP and ATP is the most active transport system in aerobic cells and is a critical component in maintaining cellular energy metabolism. 1-3 ANT is also an important component of a protein complex called the mitochondrial permeability transition (MPT) pore, the opening of which has been recognized as a key step in initiating cell death. 4 This relatively non-specific pore can open under pathologic conditions, such as elevated Ca 2+ concentration, oxidative stress, and depletion of adenine nucleotides, which are associated with events such as stroke or myocardial infarction. Pore opening allows cytoplasmic solutes less than 1500 daltons in mass to equilibrate across the inner mitochondrial membrane, causing collapse of mitochondrial membrane potential, swelling and rupture of the outer membrane, and release of toxic macromolecules that induce apoptosis. 5-7 Thus, agents that prevent MPT pore opening may provide a potentially efficacious strategy for the treatment of ischemia/reperfusion injury and for certain neurodegenerative diseases.Two different conformations of ANT have been demonstrated on the basis of interactions with specific ligands, 8 namely the inhibitors atractyloside (ATR) and bongkrekic acid (BKA) (Figure 1). These high-affinity ligands bind to ANT in an asymmetric fashion, either from the matrix (m) or from the cytosolic (c) side of the inner mitochondrial membrane, and they can mutually displace each other. Atractyloside binds to ANT in the c-conformation and induces the permeability transition, while bongkrekic acid interacts with ANT in the m-conformation and inhibits the permeability transition in response to a variety of apoptotic stimuli. 9 This finding suggests that different small molecule ligands of ANT may possess a spectrum of activities, i.e. they may act as cell protective agents targeted for acute tissue...

Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues

“…After the efficient total synthesis of BKA was established, we investigated the identification of the pharmacophore and the development of more easily available BKA analogues with potent apoptosis inhibitory activity. However, there are few reports of structure–activity relationship (SAR) studies of BKA to date,33 because of synthetic intractability, although several total syntheses of BKA have been reported. Because we were initially interested in the role of the carboxylic acid groups in BKA, four analogues, 50 – 53 , in which some of the three carboxylic acids were transformed into hydroxyl or trityl ether groups, and the structurally simplified analogue 54 , in which a methyl group on the C17 asymmetric center was removed and the alkene (C14C15) was reduced, were designed to gain a preliminary insight into the structural features that influenced the apoptosis inhibitory activity of BKA (Figure 3).…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…6; Table 3) were designed and synthesized in an attempt to find new mPT inhibitors [49,50]. Nelfinavir ( Fig.…”

Mitochondrial Drugs Come of Age

“…Dating back to the 1990s, MitoKor was one of the most significant early ventures to focus on mitochondrial approaches to treating and diagnosing disease-no doubt ahead of its time, at least in our biased view (e.g., see Howell et al [2005], , Moos et al [2008Moos et al [ , 2009, and Pei et al [2003aPei et al [ , 2003b). A wealth of knowledge regarding mitochondrial targets, structures, and disease has accumulated in the interim.…”