Efficient and Selective Demethylation of Heteroaryl Methyl Ethers in the Presence of Aryl Methyl Ethers

Soni, Ajay; Dutt, Akhilesh; Sattigeri, Viswajanani J.; Cliffe, Ian A.

doi:10.1080/00397911.2010.493262

Cited by 9 publications

(9 citation statements)

References 12 publications

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“…2-Hydroxypyridyl/pyridone compounds 26j and 26k were synthesized from methoxypyridyl precursors 26h and 26i , respectively, using nucleophilic demethylation with lithium chloride and p -toluenesulfonic acid in DMF (47–51% yield). 28 Meanwhile, 3-chloroindole derivative 27g was synthesized directly from 26g through treatment with N -chlorosuccinimide in DMF (63% yield). Synthesis of compounds 26n and 26o (Scheme 4) began with conversion of racemic alcohols 63 and 65 , respectively, to electrophilic alkylating agents.…”

Section: Resultsmentioning

confidence: 99%

Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

et al. 2019

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Mycobacterium abscessus ( Mab ) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m 1 G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab , supporting the use of TrmD as a target for the development of antimycobacterial compounds.

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Section: Resultsmentioning

confidence: 99%

Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

et al. 2019

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“…2-Hydroxypyridyl/pyridone compounds 26j and 26k were synthesized from methoxypyridyl precursors 26h and 26i respectively using nucleophilic demethylation with lithium chloride and p-toluenesulfonic acid in DMF (47-51% yield). 28 Meanwhile, 3-chloroindole derivative 27g was synthesized directly from 26g through treatment with N-chlorosuccinimide in DMF (63% yield).…”

Section: Resultsmentioning

confidence: 99%

Development of Inhibitors Against Mycobacterium Abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Whitehouse¹,

Thomas²,

Brown³

et al. 2019

Preprint

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Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria (NTM) that has emerged as a growing threat to individuals with cystic fibrosis, and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.

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“…The use of TMSI or TMSCl/NaI in MeCN24, 25 led to the deglycosylation of compound 2a and cleavage of the silyl groups, but the methyl ether remained intact. LiCl/ p ‐TsOH (5 equiv each) in N , N ‐dimethylformamide (DMF), a system that was selective for the cleavage of azaheterocyclic methyl ethers,26 caused silyl group cleavage at room temperature and product decomposition at elevated temperature. The use of EtSNa in DMF (room temperature to elevated temperature) caused the deglycosylation of compound 2a and cleavage of the silyl protecting group.…”

Section: Resultsmentioning

confidence: 99%

CC Cross‐Coupling Reactions of O⁶‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O⁶‐Deprotection Procedure

Gurram

Pottabathini

Ramesh

et al. 2012

Chemistry An Asian Journal

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Reaction conditions for the C–C cross-coupling of O6-alkyl-2-bromo- and 2-chloroinosine derivatives with aryl-, hetaryl-, and alkylboronic acids were studied. Optimization experiments with silyl-protected 2-bromo-O6-methylinosine led to the identification of [PdCl2(dcpf)]/K3PO4 in 1,4-dioxane as the best condition for these reactions (dcpf = 1,1’-bis(dicyclohexylphosphino)ferrocene). Attempted O6-demethylation, as well as the replacement of the C-6 methoxy group by amines, was unsuccessful, which led to the consideration of Pd-cleavable groups such that C–C cross-coupling and O6-deprotection could be accomplished in a single step. Thus, inosine 2-chloro-O6-allylinosine was chosen as the substrate and, after re-evaluation of the cross-coupling conditions with 2-chloro-O6-methylinosine as a model substrate, one-step C–C cross-coupling/deprotection reactions were performed with the O6-allyl analogue. These reactions are the first such examples of a one-pot procedure for the modification and deprotection of purine nucleosides under C–C cross-coupling conditions.

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Efficient and Selective Demethylation of Heteroaryl Methyl Ethers in the Presence of Aryl Methyl Ethers

Cited by 9 publications

References 12 publications

Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Development of Inhibitors Against Mycobacterium Abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

CC Cross‐Coupling Reactions of O⁶‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O⁶‐Deprotection Procedure

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Efficient and Selective Demethylation of Heteroaryl Methyl Ethers in the Presence of Aryl Methyl Ethers

Cited by 9 publications

References 12 publications

Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Development of Inhibitors Against Mycobacterium Abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

CC Cross‐Coupling Reactions of O6‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O6‐Deprotection Procedure

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Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

Development of Inhibitors against Mycobacterium abscessus tRNA (m¹G37) Methyltransferase (TrmD) Using Fragment-Based Approaches

CC Cross‐Coupling Reactions of O⁶‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O⁶‐Deprotection Procedure