138923-03-2Relevant articles and documents
Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity
Chand,Montgomery,Kotian,Dehghani,El-Kattan,Lin,Hutchison,Babu,Bantia,Elliott
, p. 4379 - 4392 (2001)
The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor - enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC50 values vs neuraminidase from influenza A and B of 50 values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.
Access to 1′-Amino Carbocyclic Phosphoramidite to Enable Postsynthetic Functionalization of Oligonucleotides
Rydzik, Anna M.,Balk, Regina,Koegler, Martin,Steinle, Tobias,Riether, Doris,Gottschling, Dirk
supporting information, p. 6735 - 6739 (2021/09/11)
We report a synthesis of a carbocyclic, abasic RNA phosphoramidite decorated with an amino functionality. The building block was efficiently incorporated into an RNA oligonucleotide in a site-specific manner, followed by deprotection to a free amino group
Substituent and solvent effects in the 1,3-dipolar cycloadditions for synthesis of anti-influenza agent peramivir and its analog
Chen, Chien-Liang,Chiu, Tzu-Wei,Chen, Yung-Wen,Fang, Jim-Min
, p. 4458 - 4470 (2019/07/03)
Influenza remains a health problem to humans. Peramivir is a FDA approved anti-influenza drug targeting the virus neuraminidase. The (3 + 2) cycloaddition reaction of 2-ethylbutanenitrile oxide with the cyclopentene dipolarophile derived from Vince lactam is a key step in the conventional synthesis of peramivir. Our study showed that conducting the (3 + 2) cycloaddition reactions with either aliphatic or aromatic nitrile oxide in hexane solution provided high percentage of the desired regioisomer, and the N-substituent having electron-withdrawing property is also beneficial to the regioselectivity. This study also demonstrated an alternative synthetic pathway of (?)-peramivir and the analog having a phenyl group in place of the 3-pentyl moiety.
Process for preparing (-)-(1S, 4R) N-protected 4-amino-2-cyclopentene-1-carboxylate esters
-
, (2008/06/13)
The invention relates to a process for preparing (?)-(1S,4R) N protected 4-amino-2-cylcopentene-1-carboxylate esters represented by the formula (I) wherein R1 and R2 are as described within the specification.