Synthesis of Leupeptins and Inhibition of Proteinases. I. Inhibition of Acrosin and Trypsin

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Abstract
A series of leupeptin analogs R-L-leucyl-L-leucyl-L-argininal with variable N-terminal substituents was synthesized using Na.alpha.-tert-butyloxycarbonyl-NG-benzyloxycarbonyl-L-arginine-.delta.-lactam as the starting material. The modified leupeptins proved to be strong competitive inhibitors of the endoprotease acrosin from mammalian [boar] spermatozoa [and bovine pancreas trypsin]. Inhibition constants were found in the range of 4.7 .times. 10-7 M (R = H) to 9.7 .times. 10-9 M (R = tert-butyloxycarbonyl). N.alpha.-tert-butyloxycarbonyl leupeptin represents the strongest acrosin inhibitor synthesized so far. Two of the leupeptin derivatives (R = trifluoroacetyl, R = tert-butyloxycarbonyl) were more effective than the natural leupeptins from microbial sources [Actinomyces sp.] (Ki = 5.9 .times. 10-8 M). The potential use of synthetic leupeptins as antienzymatic contraceptives is discussed.

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