NDLI: Three-dimensional structure-activity relationship study of belactosin A and its stereo- and regioisomers: development of potent proteasome inhibitors by a stereochemical diversity-oriented strategy

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Three-dimensional structure-activity relationship study of belactosin A and its stereo- and regioisomers: development of potent proteasome inhibitors by a stereochemical diversity-oriented strategy

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Three-dimensional structure-activity relationship study of belactosin A and its stereo- and regioisomers: development of potent proteasome inhibitors by a stereochemical diversity-oriented strategy

Content Provider	Royal Society of Chemistry (RSC)
Author	Arisawa, Mitsuhiro Unno, Yuka Yoshida, Keisuke Mizuno, Akira Yamaguchi, Kazuya Shuto, Satoshi Asai, Akira Matsuda, Akira Yokosawa, Hideyoshi Sone, Takayuki
Copyright Year	2009
Abstract	The development of potent proteasome inhibitors based on the stereochemical diversity-oriented strategy using a conformationally rigid cyclopropane structure was investigated. Thus, a series of stereo- and regioisomeric analogs of belactosin A (2), a cyclopropane amino acid (methanoamino acid)-containing tripeptidic proteasome inhibitor, were designed, in which the central cyclopropane amino acid part was replaced with the corresponding stereo- or regioisomer. Using a series of stereoisomeric cyclopropane amino acid equivalents with the cis/trans, D/L, and syn/anti stereochemical diversity, which were previously developed by us, as key units, the target compounds were successfully synthesized. Biological evaluation showed that, as expected, compound activity changed depending on the stereochemistry of the central cyclopropane amino acid part: the trans/L-syn-isomer 7 and the cis/L-anti-isomer 9 were more than twice as potent as natural belactosin A (trans/L-anti-isomer). Furthermore, the tripeptidic compound 13, the synthetic precursor for the unnatural cis/L-anti-isomer 9, was identified as a highly potent proteasome inhibitor. This compound, which is 20 times as potent as belactosin A and is even more potent than the well-known inhibitor lactacystin (4), may be an effective lead for developing clinically useful anticancer drugs. These results show that the stereochemical diversity-oriented approach can be a powerful strategy for the development of highly active compounds in medicinal chemical studies.
Starting Page	1868
Ending Page	1877
Page Count	10
File Format	HTM / HTML PDF
ISSN	14770520
Volume Number	7
Issue Number	9
Journal	Organic & Biomolecular Chemistry
DOI	10.1039/b900384c
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Duckworth\u2013Lewis method Cyclopropane Structural isomer Lactacystin Carboxylic acid Proteasome inhibitor Enzyme inhibitor Stereochemistry Proteasome
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Physical and Theoretical Chemistry

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