- A Chemoenzymatic Synthesis of the (RP)-Isomer of the Antiviral Prodrug Remdesivir
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The COVID-19 pandemic threatens to overwhelm healthcare systems around the world. The only current FDA-approved treatment, which directly targets the virus, is the ProTide prodrug remdesivir. In its activated form, remdesivir prevents viral replication by inhibiting the essential RNA-dependent RNA polymerase. Like other ProTide prodrugs, remdesivir contains a chiral phosphorus center. The initial selection of the (SP)-diastereomer for remdesivir was reportedly due to the difficulty in producing the pure (RP)-diastereomer of the required precursor. However, the two currently known enzymes responsible for the initial activation step of remdesivir are each stereoselective and show differential tissue distribution. Given the ability of the COVID-19 virus to infect a wide array of tissue types, inclusion of the (RP)-diastereomer may be of clinical significance. To help overcome the challenge of obtaining the pure (RP)-diastereomer of remdesivir, we have developed a novel chemoenzymatic strategy that utilizes a stereoselective variant of the phosphotriesterase from Pseudomonas diminuta to enable the facile isolation of the pure (RP)-diastereomer of the chiral precursor for the chemical synthesis of the (RP)-diastereomer of remdesivir.
- Bigley, Andrew N.,Narindoshvili, Tamari,Raushel, Frank M.
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- Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation
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Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.
- Gannedi, Veeranjaneyulu,Villuri, Bharath Kumar,Reddy, Sivakumar N.,Ku, Chiao-Chu,Wong, Chi-Huey,Hung, Shang-Cheng
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p. 4977 - 4985
(2021/04/02)
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- Substituted N4-hydroxycytidine derivatives and prodrug thereof for anti-novel coronavirus therapy
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The invention relates to a substituted N4-hydroxycytidine derivative with a structure as shown in a formula I, a prodrug and a pharmaceutical composition thereof, and a method of using the compositionfor the treatment of viral infections. The structure of
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Paragraph 0237-0240
(2020/08/26)
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- METHODS AND REAGENTS FOR CROSS-LINKING CELLULAR DNA AND RNA VIA STRAIN-PROMOTED DOUBLE-CLICK REACTIONS
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The present invention relates to new reagents and methods for modifying nucleic acids where an azide-containing nucleoside or nucleotide derivative is applied to living cells followed by a nitrogenous derivative of dibenzo-1,5-cyclooctadiyne (CODY). The azide- containing derivative is metabolically incorporated into cellular DNA and/or RNA, and the CODY derivative undergoes a strain-promoted double-click reaction to give nucleic acid – nucleic acid cross links, and/or optionally, in the presence of an exogenously added azide (X- N3); to give nucleic acid – "X" cross links.
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- PYRROLO[1,2-f][1,2,4]TRIAZINES USEFUL FOR TREATING RESPIRATORY SYNCITIAL VIRUS INFECTIONS
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Provided herein are formulations, methods and substituted tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds.
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Paragraph 0451-0455
(2015/05/26)
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- HCV POLYMERASE INHIBITORS
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The invention provides compounds of the formula (I) wherein B is a nucleobase selected from the groups (a) to (d): and the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 63; 64
(2015/05/05)
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- HCV Polymerase Inhibitors
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The invention provides compounds of the formula: which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Paragraph 0169; 0172; 0173
(2013/06/26)
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- HCV POLYMERASE INHIBITORS
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The invention provides compounds of the formula:(I) which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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