- Design and synthesis of galactose-conjugated fluorinated and non-fluorinated proline oligomers: Towards antifreeze molecules
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Galactose-conjugated fluorinated and non-fluorinated proline oligomers that exhibit an α-helical structure with hydrophilic and lipophilic parts were designed as potential antifreeze molecules. These galactose-proline oligomers were synthesized and their physical properties were evaluated. Interestingly, the non-fluorinated galactose-proline oligomers showed in contrast to the fluorinated analogues weak antifreeze activity. The difference in antifreeze activity should be attributed to the fluorine gauche effect, which should induce a conformation in fluorinated prolines that is different from that of natural proline. The results obtained in this study thus suggest that the 3D conformation of the galactose-conjugated fluorinated and non-fluorinated proline oligomers is very important for their anti-freezing properties.
- Sumii, Yuji,Hibino, Hayata,Saidalimu, Ibrayim,Kawahara, Hidehisa,Shibata, Norio
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supporting information
p. 9749 - 9752
(2018/09/10)
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- Practical syntheses of 4-fluoroprolines
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4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.
- Chorghade, Mukund S.,Mohapatra, Debendra K.,Sahoo, Gokarneswar,Gurjar, Mukund K.,Mandlecha, Manish V.,Bhoite, Nitin,Moghe, Santosh,Raines, Ronald T.
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experimental part
p. 781 - 784
(2009/04/04)
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- Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety
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Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24 h the antithrombin activity of the most active inhibitors with IC50s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.
- Lange, Udo E.W.,Baucke, Dorit,Hornberger, Wilfried,Mack, Helmut,Seitz, Werner,Hoeffken, H. Wolfgang
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p. 2648 - 2653
(2008/12/20)
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- Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis
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A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metath
- Yee, Nathan K.,Farina, Vittorio,Houpis, Ioannis N.,Haddad, Nizar,Frutos, Rogelio P.,Gallou, Fabrice,Wang, Xiao-Jun,Wei, Xudong,Simpson, Robert D.,Feng, Xuwu,Fuchs, Victor,Xu, Yibo,Tan, Jonathan,Zhang, Li,Xu, Jinghua,Smith-Keenan, Lana L.,Vitous, Jana,Ridges, Michael D.,Spinelli, Earl M.,Johnson, Michael,Donsbach, Kai,Nicola, Thomas,Brenner, Michael,Winter, Eric,Kreye, Paul,Samstag, Wendelin
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p. 7133 - 7145
(2007/10/03)
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- Technical scale synthesis of a new and highly potent thrombin inhibitor
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In this account, we describe the development of an efficient and convergent process for the peptidomimetic thrombin inhibitor 1 on production plant scale. Starting from nicotinonitrile (13), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2- pyrrolidinecarboxylic acid (5) and (2R)-2-amino-3-cyclohexylpropanoic acid (29) compound 1 was obtained in 16 chemical steps. New methods had been developed for the preparation of the key intermediate dehydroproline 22 and the transformation of nitriles into amidines. The thrombin inhibitor 1 was isolated by special techniques (nanofiltration and spray drying). Almost all salts of 1 are amorphous, however, a crystalline complex was obtained with 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Saccharin).
- Bernard, Harald,Buelow, Gerd,Lange, Udo E. W.,Mack, Helmut,Pfeiffer, Thomas,Schaefer, Bernd,Seitz, Werner,Zierke, Thomas
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p. 2367 - 2375
(2007/10/03)
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