First synthesis and determination of the absolute configuration of sulphostin, a novel inhibitor of dipeptidyl peptidase IV.
Sulphostin, a novel dipeptidyl peptidase IV (DPP-IV) inhibitor, was isolated from the culture broth of Streptomyces sp. MK251-43F3. Determination of the absolute configurations of two asymmetric atoms using the natural product was not achieved due to the small amount of the compound obtained. We synthesized four possible stereoisomers of sulphostin from D- or L-ornithine and compared their physicochemical and biological data to naturally isolated sulphostin. As a result, the absolute configurations at C-3 and the phosphorus atom of sulphostin were determined to be S and R, respectively, by X-ray crystallography. Synthetic sulphostin and its C-3 epimer have strong inhibitory activities against DPP-IV, IC50 values of which are 6.0 and 8.9 ng/mL, respectively. Thus it appears that the configuration of the phosphorus atom is primarily responsible for the activity; in contrast, the configuration of C-3 does not appear to affect the activity.
Abe
Masatoshi
M
Microbial Chemistry Research Center, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. abem@bikaken.or.jp
Akiyama
Tetsuo
T
Nakamura
Hikaru
H
Kojima
Fukiko
F
Harada
Shigeko
S
Muraoka
Yasuhiko
Y
D000818:Animals; D002384:Catalysis; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry; D013329:Structure-Activity Relationship
D009943:Organophosphorus Compounds; D010881:Piperidones; D011480:Protease Inhibitors; C440633:sulphostin; D018819:Dipeptidyl Peptidase 4