The Reduction of Aromatic Acids and Amides by Sodium in Liquid Ammonia

Kuehne, M. E.; Lambert, Bernard

doi:10.1021/ja01525a042

Cited by 42 publications

(7 citation statements)

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“…A series of RAPTA compounds bearing functionalized η 6 -arene ligands with potential hydrogen-bonding substituents were prepared according to the procedure depicted in Scheme . Starting from the appropriate functionalized arene, the corresponding diene is prepared via Birch reduction, and subsequent reaction with ruthenium(III) chloride in methanol under reflux affords the dinuclear chloro-bridged ruthenium complexes …”

Section: Resultsmentioning

confidence: 99%

Influence of Hydrogen-Bonding Substituents on the Cytotoxicity of RAPTA Compounds

et al. 2005

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A new series of organometallic ruthenium(II)-arene compounds of the type RuCl2(η6-arene)(phosphine) (phosphine = 1,3,5-triaza-7-phosphaadamantane, PTA, and 3,7-diacetly-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, DAPTA) with different potential hydrogen-bonding functionalities on the arene ligand have been prepared and studied for their antitumor activity. Cell viability studies using the TS/A mouse adenocarcinoma cancer cell line and the nontumorigenic HBL-100 human mammary cell line, combined with uptake determinations, are compared to the nonfunctionalized analogues, previously shown to be active on solid metastasizing tumors. The reactivity of the functionalized RAPTA compounds with a 14-mer oligonucleotide (established by mass spectrometry) has been rationalized by DFT calculations, which indicate that environmental factors are important.

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Section: Resultsmentioning

confidence: 99%

Influence of Hydrogen-Bonding Substituents on the Cytotoxicity of RAPTA Compounds

et al. 2005

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“…High-resolution mass spectra were obtained with a Micromass AutoSpec instrument using either CI or ES ionization. Compounds 1 (44), 2 (45), 3 (46), 5 (47), and 11 (48) were prepared according to reported literature procedures. Reagents and solvents were used as received from standard suppliers.…”

Section: Methodsmentioning

confidence: 99%

The Crystal Structure of BRAF in Complex with an Organoruthenium Inhibitor Reveals a Mechanism for Inhibition of an Active Form of BRAF Kinase

et al. 2009

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Substitution mutations in the BRAF serine/threonine kinase are found in a variety of human cancers. Such mutations occur in ∼70% of human malignant melanomas, and a single hyperactivating V600E mutation is found in the activation segment of the kinase domain and accounts for more than 90% of these mutations. Given this correlation, the molecular mechanism for BRAF regulation as well as oncogenic activation has attracted considerable interest, and activated forms of BRAF, such as BRAF V600E , have become attractive targets for small molecule inhibition. Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, based on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAF V600E oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAF V600E oncogene selective BRAF inhibitors for therapeutic application.RAF 1 kinases were originally identified as cellular homologues of v-raf oncogenes acquired by retroviruses and contain three members: CRAF (RAF-1 or c-RAF-1), BRAF, and ARAF (1-3). RAF family kinases are central players in the highly conserved mitogen-activated protein kinase (MAPK) signaling pathway (RAS-RAF-MEK-ERK) which relays signals from the extracellular space through receptor tyrosine kinases (RTKs) to the nucleus to promote the expression of genes involved in cell proliferation and survival. RAF kinases function by specifically phosphorylating MEK1/2 within the kinase activation loop leading to the subsequent activation of MEK1/2, which in turn activates ERK1/2. Activated ERK1/2 translocates into the nucleus and activates transcription factors to promote cellular outcomes, including survival, growth, proliferation, and differentiation (4). RAF family kinases are † This work was supported by Grant CA 114046 from the National Institutes of Health.* To whom correspondence should be addressed. Telephone: (215) 898-5006. Fax: (215) 898-0381. marmor@wistar.org. ‖ Current address: Department of Chemistry, Philipps-Universität Marburg, Marburg, Germany 1 Abbreviations: CI, chemical ionization; c-KIT, proto-oncogene receptor tyrosine kinase; DCC, dicyclohexylcarbodiimide; DCM, dichloromethane; ERK, extracellular signal-regulated kinase; ES, electrospray; FDA, Food and Drug Administration; GSK3β, glycogen synthase kinase 3 β isoform; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; MEK, dual-specificity mitogenactivated protein kinase kinase; PDB, Protein Data Bank; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol 3-kinase; RAF, RAF proto-oncogene serine/threonine-protein kinase (sub...

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“…Similarly, biaryl 10 afforded alkylated product 11b and the demethylated biaryl 11a , along with some recovered starting material (17%). In both cases, a para (in 8 ) or an ortho (in 10 ) substituent was lost during the process, a well-precedented observation on simple arenes. , This can be explained by the formation of a radical anion on the most electron-rich arene, which would then decompose into an alkoxide and a phenyl radical . The latter would then be reduced further into the corresponding anion which would be protonated by NH 3 , leading to biaryls 9a and 11a .…”

Section: Resultsmentioning

confidence: 88%

Birch Reductive Alkylation of Biaryls: Scope and Limitations

et al. 2009

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Birch reductive alkylation of biaryls has been carried out by varying the nature of the substituents on the aromatic rings. Our investigations have focused on electron-rich substituents such as OMe, OH, and NR(2) groups as they are present on the skeleton of targeted alkaloids. The regioselectivity is strongly affected by the electronic nature of these substituents on both rings. The 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and anilines do not react under these conditions. A biaryl possessing both a 3,5-dimethoxyphenyl moiety and a phenol ring may, however, be reduced and alkylated provided the acidic phenolic proton is removed prior to the treatment with Li in NH(3). Similarly, biaryls possessing a o-sulfonamide group are reduced regioselectively and alkylated with alpha-chloroacetonitrile or N-tosylaziridine to provide the corresponding dienes in reasonable to good yields. A survey of the alkylating agents was also performed showing that various functional groups may be introduced at the benzylic position, including esters, primary and tertiary amides, nitriles, epoxides, and acetals and also unfunctionalized sterically hindered t-Bu groups and cyclopropyl substituents. The introduction of the latter indicates that both a S(N)2 and a SET mechanism may take place during the alkylating step.

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The Reduction of Aromatic Acids and Amides by Sodium in Liquid Ammonia

Cited by 42 publications

References 0 publications

Influence of Hydrogen-Bonding Substituents on the Cytotoxicity of RAPTA Compounds

Influence of Hydrogen-Bonding Substituents on the Cytotoxicity of RAPTA Compounds

The Crystal Structure of BRAF in Complex with an Organoruthenium Inhibitor Reveals a Mechanism for Inhibition of an Active Form of BRAF Kinase

Birch Reductive Alkylation of Biaryls: Scope and Limitations

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