Investigation into the P3 binding domain of m-calpain using photoswitchable diazo- and triazene-dipeptide aldehydes: new anticataract agents.
The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a-d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S3 pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC50 of 35 nM). The diazo-containing inhibitors 8a, 8c, and 10a were irradiated at 340 nm to give a photostationary state enriched in the (Z)-isomer, and in all cases, these were less active. The most water soluble triazene 17a (IC50 of 90 nM) retards calpain-induced cataract formation in lens culture.
Abell
Andrew D
AD
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand. andrew.abell@canterbury.ac.nz
Jones
Matthew A
MA
Neffe
Axel T
AT
Aitken
Steven G
SG
Cain
Thomas P
TP
Payne
Richard J
RJ
McNabb
Stephen B
SB
Coxon
James M
JM
Stuart
Blair G
BG
Pearson
David
D
Lee
Hannah Y-Y
HY
Morton
James D
JD
D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002386:Cataract / Q000188:drug therapy* / Q000201:enzymology; D046508:Culture Techniques; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007908:Lens, Crystalline / Q000187:drug effects; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014226:Triazenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014466:Ultraviolet Rays
D000447:Aldehydes; D001391:Azo Compounds; D004151:Dipeptides; C521971:N-(1-formyl-3-methylbutyl)-3-methyl-2-(4-(piperidin-1-ylazo)benzenesulfonylamino)butyramide; D013449:Sulfonamides; D014226:Triazenes; D002154:Calpain; C449000:m-calpain