Bioorganic & Medicinal Chemistry Letters 2008-12-01

Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides.

Yoshio Takeuchi, Tomoya Fujiwara, Yoshihito Shimone, Hideki Miyataka, Toshio Satoh, Kenneth L Kirk, Hitoshi Hori

Index: Bioorg. Med. Chem. Lett. 18 , 6202-5, (2008)

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Abstract

In order to investigate crystallographically the mechanism of inhibition of cysteine protease by alpha-methyl-gamma,gamma-diphenylallenecarboxylic acid ethyl ester 3, a cysteine protease inhibitor having in vivo stability, we synthesized N-(alpha-methyl-gamma,gamma-diphenylallenecarbonyl)-L-phenylalanine ethyl ester 4. Reaction of 4 with thiophenol, the SH group of which has similar pK(a) value to that of cysteine protease, produced oxygen-mediated radical adducts 6 and 7 in ambient air but did not proceed under oxygen-free conditions. Catalytic activities of two thiol enzymes including cathepsin B were also lowered in the absence of oxygen. These results suggest that cysteine protease can act through an oxygen-dependent radical mechanism.