- Synthesis of D- And L-carbocyclic nucleosides via rhodium-catalyzed asymmetric hydroacylation as the key step
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(Chemical Equation Presented) D- and L-carbocyclic nucleosides were obtained by a new procedure involving an enantioselective rhodium/duphos- catalyzed hydroacylation reaction as the key step. The 3-hydroxymethyl- cyclopentanol intermediate was obtained by stereoselective reduction of ketone and by dynamic kinetic resolution (DKR).
- Marce, Patricia,Diaz, Yolanda,Matheu, M. Isabel,Castillon, Sergio
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supporting information; experimental part
p. 4735 - 4738
(2009/05/31)
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- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
- McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
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p. 7215 - 7226
(2007/10/03)
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- Bisubstrate inhibitors for the enzyme catechol O-methyltransferase (COMT): Dramatic effects of ribose modifications on binding affinity and binding mode
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Inhibition of the enzyme catechol O-methyltransferase (COMT) is of significant interest in the therapy of Parkinson's disease. Described herein are structural analogs of the potent bisubstrate inhibitor (-)-1 (IC50 = 9 nM; Table 1) for COMT, wi
- Lerner, Christian,Siegrist, Romain,Schweizer, Eliane,Diederich, Francois,Gramlich, Volker,Jakob-Roetne, Roland,Zuercher, Gerhard,Borroni, Edilio
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p. 1045 - 1062
(2007/10/03)
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- Asymmetric synthesis and antiviral activities of L-carbocyclic 2',3'- didehydro-2',3'-dideoxy and 2',3'-dideoxy nucleosides
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Asymmetric syntheses of L-carbocyclic 2',3'-didehydro-2',3'-dideoxy- and 2',3'-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S,4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2',3'-didehydro-2',3'- dideoxyadenosine (34) exhibited potent anti-HBV activity (EC50 = 0.9 μM) and moderate anti-HIV activity (EC50 = 2.4 μM) in vitro without cytotoxicity up to 100 μM.
- Wang, Peiyuan,Gullen, Beth,Newton, M. Gary,Cheng, Yung-Chi,Schinazi, Reymond F.,Chu, Chung K.
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p. 3390 - 3399
(2007/10/03)
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- Dideoxycarbocyclic nucleosides
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Antiviral and antitumor compounds are disclosed of general formula: STR1 wherein Z is H, OH or NH2, Y is CH or N, the bond indicated by C1 '--C2 ' is absent or, in combination with the C1 '--C2 ' bond is the unit CH=CH, and X is selected from the group consisting of H, N(R2), SR, OR or halogen, wherein R is H, lower (C1 -C4)alkyl, aryl or mixtures thereof, and the pharmaceutically acceptable salts thereof.
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