- Synthesis of Three-Dimensional (Di)Azatricyclododecene Scaffold and Its Application to Peptidomimetics
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A novel sp3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. Tricyclic framework 7 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one (11) via a gold(I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 12 b–e was the key to forming 6-endo-dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D-scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a–u were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a–h were synthesized as α-helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell-based assays: antiproliferative activity, HIF-1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC50=4.1±0.8 μM), whereas compounds 21 a–g showed antiviral activity with IC50 values of 4.2–12.4 μM, suggesting that the 3D-scaffold 8 a has potential as a versatile peptide mimic skeleton.
- Katoh, Akira,Kouji, Hiroyuki,Morita, Taiki,Nakamura, Hiroyuki,Umedera, Kohei,Yamada, Kentaro,Yoshimori, Atsushi
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supporting information
p. 11888 - 11894
(2021/07/06)
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- COFERONS AND METHODS OF MAKING AND USING THEM
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The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
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Page/Page column 170
(2012/12/13)
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- Biocatalytic preparation of chiral 3,4-dihydroxypyrrolidines
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Enzymatic acylations and alcoxycarbonylations of cis- and trans-3,4-dihydroxypyrrolidines and hydrolysis of their diacylated or dialcoxycarbonylated derivatives have been studied. High enantioselectivity is obtained using Candida antarctica lipase B as catalyst in the hydrolysis of the trans-diacetyl derivative, while for the desymmetrization of the cis-3,4-dihydroxypyrrolidines the best results are obtained in the acylation process catalyzed by C. antarctica lipase A.
- Rodríguez-Rodríguez, Jesús A.,Brieva, Rosario,Gotor, Vicente
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scheme or table
p. 6789 - 6796
(2010/10/03)
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- Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors
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Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice.
- Caldwell, Charles G.,Chen, Ping,He, Jiafang,Parmee, Emma R.,Leiting, Barbara,Marsilio, Frank,Patel, Reshma A.,Wu, Joseph K.,Eiermann, George J.,Petrov, Aleksandr,He, Huaibing,Lyons, Kathryn A.,Thornberry, Nancy A.,Weber, Ann E.
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p. 1265 - 1268
(2007/10/03)
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- Indolyl-urea derivatives of thienopyridines useful as antiangiogenic agents, and methods for their use
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The invention relates to compounds represented by the formula I and to prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds or said prodrugs, wherein X, R1 and R11 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula I.
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Page/Page column 22
(2010/02/05)
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- Epoxide hydrolase-catalyzed enantioselective synthesis of chiral 1,2-diols via desymmetrization of meso-epoxides
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The discovery, from nature, of a diverse set of microbial epoxide hydrolases is reported. The utility of a library of epoxide hydrolases in the synthesis of chiral 1,2-diols via desymmetrization of a wide range of meso-epoxides, including cyclic as well as acyclic alkyl- and aryl-substituted substrates, is demonstrated. The chiral (R,R)-diols were furnished with high ee's and yields. The discovery of the first microbial epoxide hydrolases providing access to complementary (S,S)-diols is also described. Copyright
- Zhao, Lishan,Han, Bin,Huang, Zilin,Miller, Mark,Huang, Hongjun,Malashock, Dan S.,Zhu, Zuolin,Milan, Aileen,Robertson, Dan E.,Weiner, David P.,Burk, Mark J.
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p. 11156 - 11157
(2007/10/03)
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- Highly enantioselective hydrolysis of alicyclic meso-epoxides with a bacterial epoxide hydrolase from Sphingomonas sp. HXN-200: Simple syntheses of alicyclic vicinal trans-diols
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Hydrolysis of N-benzyloxycarbonyl-3,4-epoxy-pyrrolidine and cyclohexene oxide with the epoxide hydrolase of Sphingomonas sp. HXN-200, respectively, gave the corresponding vicinal trans-diols in high ee and yield, representing the first example of enantioselective hydrolysis of a meso-epoxide with a bacterial epoxide hydrolase.
- Chang, Dongliang,Wang, Zunsheng,Heringa, Maarten F.,Wirthner, Renato,Witholt, Bernard,Li, Zhi
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p. 960 - 961
(2007/10/03)
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