Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition

被引：9

作者：

Annedi, SC ^{[1
]}

Majumder, K ^{[1
]}

Wei, LH ^{[1
]}

Oyiliagu, CE ^{[1
]}

Samson, S ^{[1
]}

Kotra, LP ^{[1
]}

机构：

[1] Univ Toronto, Leslie Dan Fac Pharm, Mol Design & Informat Technol Ctr, Toronto, ON M5S 2S2, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 08期

基金：

加拿大健康研究院; 加拿大创新基金会;

关键词：

fluoropeptidomimetics; protease inhibitors; chemistry and aqueous stability;

D O I：

10.1016/j.bmc.2005.02.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 PI such as compounds 15 and 16 exhibited time-dependent loss of activities against chymotrypsin, up to 67% and 79% with a K-i of 63 and 120 mu M, respectively. Fluoropeptidomimetics are a novel class of protease inhibitors and the next generation of fluoropeptidomimetics should incorporate enhanced stability. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：2943 / 2958

页数：16

共 31 条

[1] Investigation of the importance of nitrogen substituents in a N-P chiral ligand for enantioselective allylic alkylation [J].

Anderson, JC ;

Cubbon, RJ ;

Harling, JD .

TETRAHEDRON-ASYMMETRY, 2001, 12 (06) :923-935

[2] Design and synthesis of novel fluoropeptidomimetics as potential mimics of the transition state during peptide hydrolysis [J].

Annedi, SC ;

Li, WY ;

Samson, S ;

Kotra, LP .

JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (03) :1043-1049

[3] Synthesis of α-heterosubstituted glycine derivatives from dihaloethanamides [J].

Bailey, PD ;

Baker, SR ;

Boa, AN ;

Clayson, J ;

Rosair, GM .

TETRAHEDRON LETTERS, 1998, 39 (42) :7755-7758

[4] Selectfluor™ reagent F-TEDA-BF4 in action:: Tamed fluorine at your service [J].

Banks, RE .

JOURNAL OF FLUORINE CHEMISTRY, 1998, 87 (01) :1-17

[5] THE 9-FLUORENYLMETHYLOXYCARBONYL FAMILY OF BASE-SENSITIVE AMINO-PROTECTING GROUPS [J].

CARPINO, LA .

ACCOUNTS OF CHEMICAL RESEARCH, 1987, 20 (11) :401-407

[6]

Case D.A., 2002, AMBER 7

[7] A stereoselective route to hydroxyethylamine dipeptide isosteres [J].

Datta, A ;

Veeresa, G .

JOURNAL OF ORGANIC CHEMISTRY, 2000, 65 (22) :7609-7611

[8] THE DETERMINATION OF ENZYME INHIBITOR CONSTANTS [J].

DIXON, M .

BIOCHEMICAL JOURNAL, 1953, 55 (01) :170-171

[9] Selective and efficient transformation of thioethers to their sulfoxides and catalytic conversions of thiols to the disulfides with hydrated iron(III) and copper(II) nitrates in aprotic organic solvents or under solvent free conditions. [J].

Firouzabadi, H ;

Iranpoor, N ;

Zolfigol, MA .

SYNTHETIC COMMUNICATIONS, 1998, 28 (07) :1179-1187

[10]

FIRSCH MJ, 1998, GAUSSIAN 98 REVISION

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