SYNTHESIS AND PHOSPHOLIPASE A(2) INHIBITORY ACTIVITY OF THIELOCIN B3 DERIVATIVES

We prepared several types of derivatives of thielocin B3, a very poten t naturally occurring inhibitor for human nonpancreatic secretory PLA( 2) (sPLA(2)-II), and conducted a structure-activity relationship study to identify potent sPLA(2)-II inhibitors with the aim of developing a ntiinflammatory drugs. The total number of aromatic rings is critical for sPLA(2)-II inhibition, and the best result was obtained in the cas e of six rings. The structure of the central part of the inhibitors wa s not specific, and potent inhibitors were found among the sulfide, su lfone, ether, methylene, and amino derivatives. Although a diester of the terminal carboxylic acid lost its inhibitory activity, having both of the carboxylic acids was not necessary for expression of activity, as illustrated by a glycine derivative with the benzyl ester group 36 . Among the newly synthesized derivatives, 18, 20, 29, and 36 showed v ery potent human sPLA(2)-II inhibitory activity comparable to that of natural thielocin B3. Their IC50 values are in the range 0.069-0.14 mu M, and they are a class of compounds showing the most potent sPLA(2)- II inhibition to date.