Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition |
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Authors: | Annedi Subhash C Majumder Kanchana Wei Lianhu Oyiliagu Catherine E Samson Sheeba Kotra Lakshmi P |
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Affiliation: | Molecular Design and Information Technology Center, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2. |
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Abstract: | Designer fluoropeptidomimetics as protease inhibitors are revealed. The key peptidomimetic region in the inhibitors contains a '-CHF-S-' moiety and is designed to mimic the tetrahedral oxyanion species during the hydrolysis of a peptide bond. Designed fluoropeptidomimetics in aqueous methanol slowly (in several hours to days) yielded the corresponding methyl ether and/or the oxazole derivatives after cyclization. Alkyl substitutions at the C-2 position exhibited enhanced aqueous stability. Nature of '-CHF-S-' moiety and the stabilities of various fluoropeptidomimetics in aqueous solution are disclosed in detail. Fluoropeptidomimetics containing bulky substitutions at P1 such as compounds 15 and 16 exhibited time-dependent loss of activities against chymotrypsin, upto [corrected] 67% and 79% with a Ki of 63 and 120 microM, respectively. Fluoropeptidomimetics are a novel class of protease inhibitors and the next generation of fluoropeptidomimetics should incorporate enhanced stability. |
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