Synthesis of 2,3- and 3,4-methanoamino acid equivalents with stereochemical diversity and their conversion into the tripeptide proteasome inhibitor belactosin a and its highly potent cis-cyclopropane stereoisomer.
A series of chiral 2,3- and 3,4-methanoamino acid equivalents of stereochemical diversity were designed and synthesized from our chiral cyclopropane units, using a diastereoselective Grignard addition with ( R)- or ( S)- t-butanesulfinyl imines as the key step. These equivalents were converted into the proteasome inhibitor belactosin A and its cis-cyclopropane stereoisomer. The unnatural cis-isomer was shown to be more than twice as potent as belactosin A as a proteasome inhibitor.
Yoshida
Keisuke
K
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Yamaguchi
Kazuya
K
Sone
Takayuki
T
Unno
Yuka
Y
Asai
Akira
A
Yokosawa
Hideyoshi
H
Matsuda
Akira
A
Arisawa
Mitsuhiro
M
Shuto
Satoshi
S
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D003521:Cyclopropanes / Q000737:chemistry*; D036341:Intercellular Signaling Peptides and Proteins; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000596:Amino Acids; D003521:Cyclopropanes; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011480:Protease Inhibitors; C406052:belactosin A