- A Genetically Encoded Allysine for the Synthesis of Proteins with Site-Specific Lysine Dimethylation
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Using the amber suppression approach, N?-(4-azidobenzoxycarbonyl)-δ,?-dehydrolysine, an allysine precursor is genetically encoded in E. coli. Its genetic incorporation followed by two sequential biocompatible reactions allows convenient synthesis of proteins with site-specific lysine dimethylation. Using this approach, dimethyl-histone H3 and p53 proteins have been synthesized and used to probe functions of epigenetic enzymes including histone demethylase LSD1 and histone acetyltransferase Tip60. We confirmed that LSD1 is catalytically active toward H3K4me2 and H3K9me2 but inert toward H3K36me2, and methylation at p53 K372 directly activates Tip60 for its catalyzed acetylation at p53 K120.
- Wang, Zhipeng A.,Zeng, Yu,Kurra, Yadagiri,Wang, Xin,Tharp, Jeffery M.,Vatansever, Erol C.,Hsu, Willie W.,Dai, Susie,Fang, Xinqiang,Liu, Wenshe R.
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supporting information
p. 212 - 216
(2016/12/30)
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- A practical and efficient synthesis of thalidomide via Na/liquid NH 3 methodology
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A facile, efficient, concise, cost-effective, and scalable synthesis of thalidomide in high overall yield (55%) is presented. Treatment of Boc-protected L-glutamic acid diester via Na/ liquid (liq.) NH3 (-33°C) mediated cyclization methodology produces a corresponding glutarimide ring which was subsequently condensed with phthalic anhydride in the presence of glacial acetic acid to afford thalidomide.
- Varala, Ravi,Adapa, Srinivas R.
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supporting information
p. 853 - 856
(2012/12/26)
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- Thiothalidomides: Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity
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Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and mutiple myeloma and effectively reduces tumor necrosis factor-α (TNF-α) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-α and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-α inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-α secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-α secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-α mRNA stability via its 3′-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-α inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-α inhibitory activity.
- Zhu, Xiaoxiang,Giordano, Tony,Yu, Qian-Sheng,Holloway, Harold W.,Perry, Tracy Ann,Lahiri, Debomoy K.,Brossi, Arnold,Greig, Nigel H.
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p. 5222 - 5229
(2007/10/03)
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