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Cyclic Histones

Figure 1.8 Structures 66 to 79 Cyclic Histone Deacetylase Inhibitors. Figure 1.8 Structures 66 to 79 Cyclic Histone Deacetylase Inhibitors.
One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. [Pg.280]

Furumai R, Komatsu Y, Nishino N, Khochbin S, Yoshida M, Horinouchi S (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc Natl Acad Sci U S A 98(l) 87-92... [Pg.287]

Nakao Y, Yoshida S, Matsunaga S, Shindoh N, Terada Y, Nagai K, Yamashita JK, Ganesan A, van Soest RWM, Fusetani N. (2006) Azumamides A-E Histone deacetylase inhibitory cyclic tetrapeptides from the marine spong Mycale izuensis. Angew Chem Int Ed 45 7553-7557. [Pg.303]

Kijima M, Yoshida M, Susita K, Horinouchi S, Beppu T. (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 30 22429-22435. [Pg.306]

Komatsu, Y, Tomizaki, K., Tsukamoto, M., Kato, T, Nishino, N., Sato, S. et al. (2001) Cyclic hydroxamic-add-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Research, 61, 4459 466. [Pg.222]

Nishino, N., Jose, B., Okamura, S., Ebisusaki, S., Kato, T, Sumida, Y. et al. (2003) Cyclic tetrapeptides bearing a sulfhydryl group potently inhibit histone deacetylases. Organic Letters, 5,5079-5082. [Pg.222]

Many other kinases have been studied, often in the context of regulation of some process by phosphorylation and dephosphorylation. Examples from muscle regulation have already been given. A further example is the transcription of eukaryotic DNA, which may be regulated by phosphorylation of non-histone chromosomal proteins. A number of nuclear protein kinases have been partially purified. These have an absolute requirement for divalent cations, and are not stimulated by 3, 5 -cyclic AMP (cAMP).287,288... [Pg.580]

Brown s crotylboration protocol was used effectively in the synthesis of azu-mamide A 28. Azumamides are unusual cyclic peptides that show potent inhibitory activity on histone deacetylase enzymes. A highly diastereo- and enan-tioselective (dr >99% 98% ee) crotylation of 3-benzyloxypropanal with the chiral reagent ( >crotyl-1Ipc2borane (l19E) afforded the homoallylic alcohol 29. Subsequent reductive ozonolysis and K2CO3-mediated hydrolysis of the acetate furnished the diol 3016 (Scheme 3.1m). [Pg.113]

The molecular basis for regulation of enzymatic activity through phosphorylation and dephosphorylation has been established in many enzyme systems (29). The significance of these reactions in histones, ribosomal proteins and KNA polymerase is not known. In an attempt to establish the specificity of the cyclic AMP-dependent protein kinases, the structure of several substrates have been determined (30). The data indicate that the sequence around the phosphorylated serine residue all contain two basic amino acids separated by no more than two residues from the N-terminal of the susceptible serine (e.g. -Arg-Arg-X-Y-Ser-). [Pg.55]

Bromotyrosine-derived metabolites are often encountered in marine sponges of the families Aplysinidae and Pseudocer-atidae, in particular Pseudoceratina (= Psammaplysilla) purpurea. They show a variety of biological activities, which include antimicrobial, enzyme inhibitory, and antifouling activities. Psammaplysin A (47) is antimicrobial, cytotoxic, and antifouling, whereas psammaplin A (48) is an inhibitor of histone deacetylase (2). The marine sponge lanthella basta synthesizes at least 25 bastadins that are linear or cyclic peptides composed of four bromotyrosine residues [bastadin 5 (49)] and show antimicrobial, cytotoxic, and enzyme inhibitory activities as well as interaction with Ca + channels (21). [Pg.1161]

Singh SB, Zink DL, Liesch JM, Mosley RT, Dombrowski AW, Bills GP, Darkin-Rattray SJ, Schmatz DM, Goetz MA. Structure and chemistry of apicidins, a class of novel cyclic tetrapeptides without a terminal alpha-keto epoxide as inhibitors of histone deacetylase with potent antiprotozoal activities. J. Org. Chem. 2002 67 815-825. [Pg.1479]

The method is based upon the ability of low concentrations of cyclic nucleotides to activate protein kinases which catalyse the phosphorylation of protein substrates, such as histone, by ATP [156,157]. The extent of phosphorylation is proportional to the amount of the cyclic nucleotides. The limits of sensitivity of the method are about 0.3 pmol for cyclic AMP and 0.5 pmol for cyclic GMP. Purification on a Dowex 50 column separates the two cyclic nucleotides from each other and removes any substances, such as ATP, which might interfere with the assay. Cyclic GMP is further purified by column chromatography on aluminum oxide and Dowex 1. Cyclic AMP-activated protein kinase is prepared from bovine heart and cyclic GMP-activated protein kinase from lobster tail. [Pg.318]

For the cyclic AMP assay [y- P]ATP (10 uM) is incubated with 10 mM magnesium acetate, cyclic AMP standard (0-10 pmol) or water, histone mixture, cyclic AMP-activated protein kinase, and 0.1 M sodium acetate buffer, pH 6.0, for 5 min at 30°C. The reaction is terminated by the addition of trichloroacetic-acid-tungstate-sulfuric acid, the precipitate is dissolved in N NaOH, and the radioactivity counted in scintillation fluid. [Pg.318]

Montero A et al (2009) Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures. J Am Chem Soc 131(8) 3033—3041... [Pg.45]


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See also in sourсe #XX -- [ Pg.530 ]




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Cyclic Histone Deacetylase Inhibitors (HDACs)

Histone

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