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Synthesis 2003(11): 1717-1721
DOI: 10.1055/s-2003-40876
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Design and Combinatorial Synthesis of N-Acyl Iminodiacetic Acids as Bongkrekic Acid Analogues for the Inhibition of Adenine Nucleotide Translocase

Yazhong Pei*, Amy K. Carroll, Christen M. Anderson, Walter H. Moos, Soumitra S. Ghosh
MitoKor, Inc., 11494 Sorrento Valley Road, San Diego, CA 92121, USA
Fax: +1(858)5095700; e-Mail: peiy@mitokor.com;
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Publication History

Received 7 May 2003
Publication Date:
25 July 2003 (online)

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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.

Key words

bongkrekic acid - mitochondria - library design - combinatorial synthesis - N-acyl iminodiacetic acids