共查询到20条相似文献,搜索用时 15 毫秒
1.
Nishino N Shivashimpi GM Soni PB Bhuiyan MP Kato T Maeda S Nishino TG Yoshida M 《Bioorganic & medicinal chemistry》2008,16(1):437-445
Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that effect gene regulation. To know the interaction of aliphatic cap groups with HDACs, cyclic tetrapeptide and bicyclic peptide disulfide hybrids were synthesized without aromatic ring in their macrocyclic framework. Benzene ring of l-Phe in chlamydocin was replaced with several aliphatic amino acids and also a fused bicyclic tetrapeptide was synthesized by ring closing metathesis using Grubb's first generation catalyst. The inhibitory activities of the cyclic peptides against histone deacetylase enzymes were evaluated, which demonstrated most of them are interesting candidates as anticancer agents. 相似文献
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Nishino N Jose B Shinta R Kato T Komatsu Y Yoshida M 《Bioorganic & medicinal chemistry》2004,12(22):5777-5784
Chlamydocin-hydroxamic acid analogues were designed and synthesized as histone deacetylase (HDAC) inhibitors based on the structure and HDAC inhibitory activity of chlamydocin and trichostatin A. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone moiety in the side chain that makes it an irreversible inhibitor of HDAC. We replaced the epoxyketone moiety of chlamydocin with hydroxamic acid to design potent and reversible inhibitors of HDAC. In addition, a number of amino-cycloalkanecarboxylic acids (Acc) are introduced instead of the simple amino-isobutric acid (Aib) for a variety of the series of chlamydocin analogues. The compounds synthesized were tested for HDAC inhibitory activity and the results showed that many of them are potent inhibitors of HDAC. The replacement of Aib residue of chlamydocin with an aromatic amino acid enhances the in vivo and in vitro inhibitory activity. We have carried out circular dichroism and molecular modeling studies on chlamydocin-hydroxamic acid analogue and compared it with the solution structure of chlamydocin. 相似文献
3.
Bhuiyan MP Kato T Okauchi T Nishino N Maeda S Nishino TG Yoshida M 《Bioorganic & medicinal chemistry》2006,14(10):3438-3446
A series of chlamydocin analogs with various carbonyl functionalities were designed and synthesized as histone deacetylase (HDAC) inhibitors. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone surrogate in the side chain which makes it irreversible inhibitor of HDACs, whereas apicidins are a class of cyclic tetrapeptides that contain an ethylketone moiety as zinc ligand. We replaced the epoxyketone moiety of chlamydocin with several ketones and aldehyde to synthesize potent reversible and selective HDAC inhibitors. The inhibitory activity of the cyclic tetrapeptides against histone deacetylase enzymes were evaluated and the result showed most of them are potent inhibitors. Some of them have remarkable selectivity among the HDACs. 相似文献
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Islam MS Bhuiyan MP Islam MN Nsiama TK Oishi N Kato T Nishino N Ito A Yoshida M 《Amino acids》2012,42(6):2103-2110
The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, l-phenylalanine, d-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition. 相似文献
5.
The structure and conformation of HC-toxin 总被引:2,自引:0,他引:2
M Kawai D H Rich J D Walton 《Biochemical and biophysical research communications》1983,111(2):398-403
Difference nuclear magnetic resonance studies and amino acid oxidase experiments establish the sequence and configuration of amino acids in HC-toxin as cyclo(L-Aoe-D-Pro-L-Ala-D-Ala). HC-toxin adopts the bis-γ-turn conformation in solution previously found for the cytostatic cyclic tetrapeptide chlamydocin. 相似文献
6.
Jose B Okamura S Kato T Nishino N Sumida Y Yoshida M 《Bioorganic & medicinal chemistry》2004,12(6):1351-1356
A cyclic hexapeptide hydroxamic acid inhibitor for HDAC6 has been designed and synthesized on the basis of the facts that alpha-tubulin is the substrate of HDAC6 and of the excellent inhibitory activity of cyclic tetrapeptide hydroxamic acids (CHAPs) for HDACs. Unexpectedly, cyclic hexapeptide hydroxamic acid showed very low HDAC inhibitory activity. To explain the low activity, we have carried out conformation analysis and compared it to the crystal structure of alpha-tubulin. The conformation around the acetylated lysine of the cyclic hexapeptide substrate or the aminosuberate hydroxamic acid [Asu(NHOH)] of cyclic hexapeptide inhibitor is different from that around alpha-tubulin's lysine-40. The difference in the conformation seems to cause some steric hindrance at the capping site resulting in poor binding capacity. 相似文献
7.
Lavoie R Bouchain G Frechette S Woo SH Abou-Khalil E Leit S Fournel M Yan PT Trachy-Bourget MC Beaulieu C Li Z Besterman J Delorme D 《Bioorganic & medicinal chemistry letters》2001,11(21):2847-2850
Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities. 相似文献
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D H Rich M Kawai R D Jasensky 《International journal of peptide and protein research》1983,21(1):35-42
The conformations of chlamydocin and cyclo (Ala-Aib-Phe-D-Pro) (Ala4-chlamydocin) in chloroform have been investigated by nuclear magnetic resonance, infrared and circular dichroism spectroscopy. The data obtained from these experiments establish an all transoid, bis gamma-turn conformation for both compounds in chloroform with the following torsional angles (+/- 20 degrees): Ala4-chlamydocin: Aib, phi + 60 degrees, psi - 50 degrees; omega + 160 degrees; Phe phi - 120 degrees, psi + 120 degrees, omega - 160 degrees; D-Pro phi + 60 degrees, psi - 55 degrees, omega + 160 degrees; Ala phi - 110 degrees, psi + 110 degrees, omega - 160 degrees. Chlamydocin adopts a closely related conformation in neat chloroform. Nuclear Overhauser Effect (NOE) data are utilized to assign amide bond geometries in the cyclic tetrapeptide ring system. 相似文献
10.
Subha Kalyaanamoorthy Yi-Ping Phoebe Chen 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(1):317-328
Histone deacetylases (HDACs) are important class of enzymes that deacetylate the ε-amino group of the lysine residues in the histone tails to form a closed chromatin configuration resulting in the regulation of gene expression. Inhibition of these HDACs enzymes have been identified as one of the promising approaches for cancer treatment. The type-specific inhibition of class I HDAC enzymes is known to elicit improved therapeutic effects and thus, the search for promising type-specific HDAC inhibitors compounds remains an ongoing research interest in cancer drug discovery. Several different strategies are employed to identify the features that could identify the isoform specificity factors in these HDAC enzymes. This study combines the insilico docking and energy-optimized pharmacophore (e-pharmacophore) mapping of several known HDACi's to identify the structural variants that are significant for the interactions against each of the four class I HDAC enzymes. Our hybrid approach shows that all the inhibitors with at least one aromatic ring in their linker regions hold higher affinities against the target enzymes, while those without any aromatic rings remain as poor binders. We hypothesize the e-pharmacophore models for the HDACi's against all the four Class I HDAC enzymes which are not reported elsewhere. The results from this work will be useful in the rational design and virtual screening of more isoform specific HDACi's against the class I HDAC family of proteins. 相似文献
11.
Dawei Huang Xiaohui Li Lei Sun Zhilong Xiu Norikazu Nishino 《Journal of peptide science》2012,18(4):242-251
Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(?l ‐Am7(S2Py)‐Aib‐l ‐Phe(n‐Me)‐d ‐Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC50 in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
12.
Jones P Altamura S Chakravarty PK Cecchetti O De Francesco R Gallinari P Ingenito R Meinke PT Petrocchi A Rowley M Scarpelli R Serafini S Steinkühler C 《Bioorganic & medicinal chemistry letters》2006,16(23):5948-5952
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates. 相似文献
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Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors 总被引:1,自引:0,他引:1
Khan N Jeffers M Kumar S Hackett C Boldog F Khramtsov N Qian X Mills E Berghs SC Carey N Finn PW Collins LS Tumber A Ritchie JW Jensen PB Lichenstein HS Sehested M 《The Biochemical journal》2008,409(2):581-589
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Histone deacetylases (HDACs) are a promising target for treating cancer and some other disorders. Herein, based on the structure of our previously reported tetrahydroisoquinoline-based hydroxamic acids, a novel series of tyrosine-based hydroxamic acid derivatives was designed and synthesized as HDACs inhibitors. Compared with tetrahydroisoquinoline-based hydroxamic acids, tyrosine-based hydroxamic acid derivatives exhibited more potent HDAC8 inhibitory activity. However, the antiproliferative activities and HeLa cell nuclear extract inhibition of several selected tyrosine-based hydroxamic acids were moderate. 相似文献
18.
Suzuki T Kouketsu A Matsuura A Kohara A Ninomiya S Kohda K Miyata N 《Bioorganic & medicinal chemistry letters》2004,14(12):3313-3317
In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated. Compound 6, in which the hydroxamic acid of SAHA was replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. 相似文献
19.
Witter DJ Harrington P Wilson KJ Chenard M Fleming JC Haines B Kral AM Secrist JP Miller TA 《Bioorganic & medicinal chemistry letters》2008,18(2):726-731
A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model. 相似文献
20.
Sundarapandian Thangapandian Shalini John Yuno Lee Venkatesh Arulalapperumal Keun Woo Lee 《PloS one》2012,7(11)
Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively. We have identified the equivalent tunnel forming amino acids in these three isoforms and found that they are very much conserved with subtle differences to be utilized in selective inhibitor development. One amino acid, methionine of HDAC8, among six tunnel forming residues is different in isoforms of other classes (glutamic acid (E) in HDAC10 and leucine (L) in HDAC 11) based on which mutations were introduced in HDAC11, the less studied HDAC isoform, to observe the effects of this change. The HDAC8-like (L268M) mutation in the tunnel forming residues has almost maintained the deep and narrow tunnel as present in HDAC8 whereas HDAC10-like (L268E) mutation has changed the tunnel wider and shallow as observed in HDAC10. These results explained the importance of the single change in the tunnel formation in different isoforms. The observations from this study can be utilized in the development of isoform-selective HDAC inhibitors. 相似文献