102728-48-3Relevant academic research and scientific papers
Design of gem-difluoro-bis-tetrahydrofuran as p2 ligand for HIV-1 protease inhibitors to improve brain penetration: Synthesis, x-ray studies, and biological evaluation
Ghosh, Arun K.,Yashchuk, Sofiya,Mizuno, Akira,Chakraborty, Nilanjana,Agniswamy, Johnson,Wang, Yuan-Fang,Aoki, Manabu,Gomez, Pedro Miguel Salcedo,Amano, Masayuki,Weber, Irene T.,Mitsuya, Hiroaki
, p. 107 - 115 (2015)
The structure-based design, synthesis, biological evaluation, and X-ray structural studies of fluorine-containing HIV-1 protease inhibitors are described. The synthesis of both enantiomers of the gem-difluoro-bis-THF ligands was carried out in a stereoselective manner using a Reformatskii-Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((Nisobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl) carbamate (3) and (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-aminophenyl)sulfonamido)phenylbutan-2-yl) carbamate (4), exhibited HIV-1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV-1LAI· The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood-brain barrier permeability in an in vitro model. A high-resolution X-ray structure of inhibitor 4 in complex with HIV-1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV-1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis-THF ligand formed strong interactions with the flap Gly48 carbonyl oxygen atom.
HIV-1 PROTEASE INHIBITORS HAVING GEM-DI-FLUORO BICYCLIC P2-LIGANDS
-
Paragraph 0102, (2015/03/16)
Various embodiments of the present invention relate to, among other things, compounds and methods of using those compounds to treat an HIV infection. The compounds of the various embodiments of the present invention provide, among other things, therapeutic agents having enhanced penetration capability across the blood-brain barrier, such that they can enter the CNS to treat an HIV-1 infection in the CNS.
Highly convergent stereoselective synthesis of chiral key intermediates in the synthesis of Palinavir from imines derived from L-glyceraldehyde
Badorrey, Ramón,Cativiela, Carlos,Díaz-De-Villegas, María D,Gálvez, José A
, p. 341 - 354 (2007/10/03)
Imines derived from O-protected (S)-glyceraldehyde are valuable intermediates in the synthesis of different kinds of amino acids. We have developed a highly convergent and stereoselective method to obtain (2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butylamine and (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic acid tert-butylamide, which are key intermediates in the synthesis of Palinavir, that consist in the treatment of the appropriate imine with benzylmagnesium bromide and Danishefsky's diene, respectively, and subsequent transformation of the obtained adducts into the desired compounds. The reaction of N-benzylimine derived from (S)-2,3-di-O-benzylglyceraldehyde with benzylmagnesium bromide is completely diastereoselective at low temperature. Hetero Diels-Alder reaction of imine derived from (S)-2,3-di-O-benzylglyceraldehyde and (R)-N-α-methylbenzylamine is completely diastereoselective at low temperature in the presence of ZnI2.
Diastereoselectivity in Organometallic Additions to the Carbonyl Group of Protected Erythrulose Derivatives
Alberto Marco,Carda, Miguel,Gonzalez, Florenci,Rodriguez, Santiago,Castillo, Encarna,Murga, Juan
, p. 698 - 707 (2007/10/03)
We have investigated a number of nucleophillic additions to L-erythrulose derivatives (4-12) bearing protective O-silyl, O-benzyl, and O-trityl groups in various relative positions. The results are discussed in the frame of chelated vs nonchelated transit
Asymmetric synthesis by the use of norephedrine-derived 2-methoxy-oxazolidines. Part four: the synthesis of enantiomerically enriched polyhydroxylated building blocks
Bernardi, A.,Piarulli, U.,Poli, G.,Scolastico, C.,Villa, R.
, p. 751 - 757 (2007/10/02)
The Lewis acid promoted addition of five silylketeneacetals to norephedrine derived 2-methoxy oxazolidines allowed the stereoselective incorporation of an oxy function vicinal to the oxazolidinic C-2 position.Subsequent functional group modification and/or non destructive chirophor removal, afforded enantiomerically enriched polyhydroxylated building blocks such as (S)-di-O-benzyl glyceraldehyde and D-ribose propane-1,3 diyldithioacetal.A rational accounting for the selectivity of the coupling steps is proposed.Keywords: asymmetric synthesis / norephedrine / (S)-di-O-benzylglyceraldehyde / D-ribose propane-1,3-diyldithioacetal
MICROBIOLOGICAL SYNTHESIS OF VARIOUSLY PROTECTED L-GLYCERALDEHYDES IN HIGH OPTICAL PURITY
Guanti, Giuseppe,Banfi, Luca,Narisano, Enrica
, p. 3547 - 3550 (2007/10/02)
Variously protected L-glyceraldehydes have been enantioselectively synthesized through a sequence involving acylation of formylanion equivalents with glycolic acid derivatives followed by baker's yeast mediated reduction of the resulting ketones.
