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1.
Bieliauskas AV Weerasinghe SV Pflum MK 《Bioorganic & medicinal chemistry letters》2007,17(8):2216-2219
Inhibitors of histone deacetylase (HDAC) proteins such as suberoylanilide hydroxamic acid (SAHA) have emerged as effective therapeutic anti-cancer agents. To better understand the structural requirements of HDAC inhibitors, a small molecule library with a variety of substituents attached adjacent to the metal binding hydroxamic acid of SAHA was synthesized. The presence of a substituent adjacent to the hydroxamic acid led to an 800- to 5000-fold decrease in inhibition compared to SAHA. The observed results have implications for drug design, suggesting that HDAC inhibitors with substituents near the metal binding moiety will have inhibitory activities in the micromolar rather than nanomolar range. 相似文献
2.
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
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《Autophagy》2013,9(10):1521-1522
Cells respond to cytotoxicity by activating a variety of signal transduction pathways. One pathway frequently upregulated during cytotoxic response is macroautophagy (hereafter referred to as autophagy). Previously, we demonstrated that pan-histone deacetylase (HDAC) inhibitors, such as the anticancer agent suberoylanilide hydroxamic acid (SAHA, Vorinostat), can induce autophagy. In this study, we show that HDAC inhibition triggers autophagy by suppressing MTOR and activating the autophagic kinase ULK1. Furthermore, autophagy inhibition can sensitize cells to both apoptotic and nonapoptotic cell death induced by SAHA, suggesting the therapeutic potential of autophagy targeting in combination with SAHA therapy. This study also raised a series of questions: What is the role of HDACs in regulating autophagy? Do individual HDACs have distinct functions in autophagy? How do HDACs regulate the nutrient-sensing kinase MTOR? Since SAHA-induced nonapoptotic cell death is not driven by autophagy, what then is the mechanism underlying the apoptosis-independent death? Tackling these questions should lead to a better understanding of autophagy and HDAC biology and contribute to the development of novel therapeutic strategies. 相似文献
5.
Cells respond to cytotoxicity by activating a variety of signal transduction pathways. One pathway frequently upregulated during cytotoxic response is macroautophagy (hereafter referred to as autophagy). Previously, we demonstrated that pan-histone deacetylase (HDAC) inhibitors, such as the anticancer agent suberoylanilide hydroxamic acid (SAHA, Vorinostat), can induce autophagy. In this study, we show that HDAC inhibition triggers autophagy by suppressing MTOR and activating the autophagic kinase ULK1. Furthermore, autophagy inhibition can sensitize cells to both apoptotic and nonapoptotic cell death induced by SAHA, suggesting the therapeutic potential of autophagy targeting in combination with SAHA therapy. This study also raised a series of questions: What is the role of HDACs in regulating autophagy? Do individual HDACs have distinct functions in autophagy? How do HDACs regulate the nutrient-sensing kinase MTOR? Since SAHA-induced nonapoptotic cell death is not driven by autophagy, what then is the mechanism underlying the apoptosis-independent death? Tackling these questions should lead to a better understanding of autophagy and HDAC biology and contribute to the development of novel therapeutic strategies. 相似文献
6.
《Bioorganic & medicinal chemistry》2014,22(21):5766-5775
A series of 1,3,4-thiadiazole-containing hydroxamic acids, in accord with the common pharmacophore of histone deacetylase (HDAC) inhibitors (a Zn2+ binding moiety–a linker–a surface recognition motif), was identified as submicromolar HDAC inhibitors by our group. In this study, we continued our efforts to develop 1,3,4-thiadiazole bearing hydroxamate analogues by modifying the surface recognition motif. We found that 1,3,4-thiadiazoles having a heteroaromatic substituent showed better HDAC inhibitory activity in enzymatic assay and higher antiproliferative potency in cellular assay compared to SAHA. 相似文献
7.
Dhimant Desai Ugur Salli Kent E. Vrana Shantu Amin 《Bioorganic & medicinal chemistry letters》2010,20(6):2044-2047
Cancer treatment and therapy has moved from conventional chemotherapeutics to more mechanism-based targeted approach. Disturbances in the balance of histone acetyltransferase (HAT) and deacetylase (HDAC) leads to a change in cell morphology, cell cycle, differentiation, and carcinogenesis. In particular, HDAC plays an important role in carcinogenesis and therefore it has been a target for cancer therapy. Structurally diverse group of HDAC inhibitors are known. The broadest class of HDAC inhibitor belongs to hydroxamic acid derivatives that have been shown to inhibit both class I and II HDACs. Suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA), which chelate the zinc ions, fall into this group. In particular, SAHA, second generation HDAC inhibitor, is in several cancer clinical trials including solid tumors and hematological malignancy, advanced refractory leukemia, metastatic head and neck cancers, and advanced cancers. To our knowledge, selenium-containing HDAC inhibitors are not reported in the literature. In order to find novel HDAC inhibitors, two selenium based-compounds modeled after SAHA were synthesized. We have compared two selenium-containing compounds; namely, SelSA-1 and SelSA-2 for their inhibitory HDAC activities against SAHA. Both, SelSA-1 and SelSA-2 were potent HDAC inhibitors; SelSA-2 having IC50 values of 8.9 nM whereas SAHA showed HDAC IC50 values of 196 nM. These results provided novel selenium-containing potent HDAC inhibitors. 相似文献
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Joshua C. Canzoneri Po C. Chen Adegboyega K. Oyelere 《Bioorganic & medicinal chemistry letters》2009,19(23):6588-6590
We describe herein the synthesis and characterization of a new class of histone deacetylase (HDAC) inhibitors derived from conjugation of a suberoylanilide hydroxamic acid-like aliphatic-hydroxamate pharmacophore to a nuclear localization signal peptide. We found that these conjugates inhibited the histone deacetylase activities of HDACs 1, 2, 6, and 8 in a manner similar to suberoylanilide hydroxamic acid (SAHA). Notably, compound 7b showed a threefold improvement in HDAC 1/2 inhibition, a threefold increase in HDAC 6 selectivity and a twofold increase in HDAC 8 selectivity when compared to SAHA. 相似文献
10.
Byungchul Kim Amit S. Pithadia Carol A. Fierke 《Protein science : a publication of the Protein Society》2015,24(3):354-365
Histone deacetylase 8 (HDAC8) was originally classified as a Zn(II)-dependent deacetylase on the basis of Zn(II)-dependent HDAC8 activity in vitro and illumination of a Zn(II) bound to the active site. However, in vitro measurements demonstrated that HDAC8 has higher activity with a bound Fe(II) than Zn(II), although Fe(II)-HDAC8 rapidly loses activity under aerobic conditions. These data suggest that in the cell HDAC8 could be activated by either Zn(II) or Fe(II). Here we detail the kinetics, thermodynamics, and selectivity of Zn(II) and Fe(II) binding to HDAC8. To this end, we have developed a fluorescence anisotropy assay using fluorescein-labeled suberoylanilide hydroxamic acid (fl-SAHA). fl-SAHA binds specifically to metal-bound HDAC8 with affinities comparable to SAHA. To measure the metal affinity of HDAC, metal binding was coupled to fl-SAHA and assayed from the observed change in anisotropy. The metal KD values for HDAC8 are significantly different, ranging from picomolar to micromolar for Zn(II) and Fe(II), respectively. Unexpectedly, the Fe(II) and Zn(II) dissociation rate constants from HDAC8 are comparable, koff ∼0.0006 s−1, suggesting that the apparent association rate constant for Fe(II) is slow (∼3 × 103 M−1 s−1). Furthermore, monovalent cations (K+ or Na+) that bind to HDAC8 decrease the dissociation rate constant of Zn(II) by ≥100-fold for K+ and ≥10-fold for Na+, suggesting a possible mechanism for regulating metal exchange in vivo. The HDAC8 metal affinities are comparable to the readily exchangeable Zn(II) and Fe(II) concentrations in cells, consistent with either or both metal cofactors activating HDAC8. 相似文献
11.
Raushan K. Singh Tanmay Mandal Narayanaganesh Balasubramanian Gregory Cook D.K. Srivastava 《Analytical biochemistry》2011,(2):309
Histone deacetylases (HDACs) are intimately involved in epigenetic regulation and, thus, are one of the key therapeutic targets for cancer, and two HDAC inhibitors, namely suberoylanilide hydroxamic acid (SAHA) and romidepsin, have been recently approved for cancer treatment. Because the screening and detailed characterization of HDAC inhibitors has been time-consuming, we synthesized coumarin-SAHA (c-SAHA) as a fluorescent probe for determining the binding affinities (Kd) and the dissociation off-rates (koff) of the enzyme–inhibitor complexes. The determination of the above parameters relies on the changes in the fluorescence emission intensity (λex = 325 nm, λem = 400 nm) of c-SAHA due to its competitive binding against other HDAC inhibitors, and such determination neither requires employment of polarization accessories nor is dependent on the fluorescence energy transfer from the enzyme’s tryptophan residues to the probe. Our highly sensitive and robust analytical protocol presented here is applicable to most of the HDAC isozymes, and it can be easily adopted in a high-throughput mode for screening the HDAC inhibitors as well as for quantitatively determining their Kd and koff values. 相似文献
12.
Ahmed T. Negmeldin Mary Kay H. Pflum 《Bioorganic & medicinal chemistry letters》2017,27(15):3254-3258
Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity. C5-modified SAHA analogs displayed dual selectivity to HDAC6 and HDAC8 over HDAC 1, 2, and 3, with only a modest reduction in potency. These findings are consistent with prior work showing that modification of the linker region of SAHA can alter isoform selectivity. The observed HDAC6/8 selectivity of C5-modified SAHA analogs provide guidance toward development of isoform selective HDAC inhibitors and more effective anti-cancer drugs. 相似文献
13.
Quinazoline‐Based Hydroxamic Acids: Design,Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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Doan Thanh Hieu Duong Tien Anh Pham‐The Hai Le‐Thi‐Thu Huong Eun Jae Park Jeong Eun Choi Jong Soon Kang Phan Thi Phuong Dung Sang‐Bae Han Nguyen‐Hai Nam 《化学与生物多样性》2018,15(6)
In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N‐hydroxybenzamides incorporating quinazoline heterocycles ( 4a – 4i , 6a – 6i ). Bioevaluation showed that these quinazoline‐based hydroxamic acids and N‐hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI‐H23, lung). In term of cytotoxicity, several compounds, e.g., 4g , 4c , 4g – 4i , 6c , and 6h , displayed from 5‐ up to 10‐fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub‐micromolar range. Some compounds, e.g., 4g , 6c , 6e , and 6h , were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g , 6c , and 6g , while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates. 相似文献
14.
Nilkamal Karelia Dhimant Desai Jeremy A. Hengst Shantu Amin Sairam V. Rudrabhatla Jong Yun 《Bioorganic & medicinal chemistry letters》2010,20(22):6816-6819
Cancer therapy has moved beyond conventional chemotherapeutics to more mechanism-based targeted approaches. Studies demonstrate that histone deacetylase (HDAC) is a promising target for anticancer agents. Numerous, structurally diverse, hydroxamic acid derivative, HDAC inhibitors have been reported and have been shown to induce growth arrest, differentiation, autophagy, and/or apoptotic cell death by inhibiting multiple signaling pathways in cancer cells. Suberoylanilide hydroxamic acid (SAHA) has emerged as an effective anticancer therapeutic agent and was recently approved by the FDA for the treatment of advanced cutaneous T-cell lymphoma. In our previous study, we reported the development of the novel, potent, selenium-containing HDAC inhibitors (SelSA-1 and SelSA-2). In this study, the effects of SelSA-1 and SelSA-2 on signaling pathways and cytotoxicity were compared with the known HDAC inhibitor, SAHA, in lung cancer cell lines. After 24 h of treatment, SelSA-1 and SelSA-2 inhibited lung cancer cell growth to a greater extent than SAHA in a dose-dependent manner with IC50 values at low micromolar concentrations. SelSA-1 and SelSA-2 inhibited ERK and PI3K-AKT signaling pathways while simultaneously increasing in autophagy in A549 cells in a time dependent manner. This preliminary study demonstrates the effectiveness of the selenium-containing analogs of SAHA, SelSA-1, and SelSA-2, as HDAC inhibitors and provides insight into the improvement and/or development of these analogs as a therapeutic approach for the treatment of lung cancer. 相似文献
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Wang Y Wang SY Zhang XH Zhao M Hou CM Xu YJ Du ZY Yu XD 《Biochemical and biophysical research communications》2007,356(4):998-1003
Some pan-histone-deacetylase (HDAC) inhibitors have recently been reported to exert their anti-leukemia effect by inhibiting the activity of class IIB HDAC6, which is the deacetylase of Hsp90 and α-tubulin, thereby leading to hyperacetylation of Hsp90, disruption of its chaperone function and apoptosis. In this study, we compared the effect of a class I HDAC inhibitor FK228 with the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on the Hsp90 chaperone function of K562 cells. We demonstrated that, although having a weaker inhibitory effect on HDAC6, FK228 mediated a similar disruption of Hsp90 chaperone function compared to SAHA. Unlike SAHA, FK228 did not mediate hyperacetylation of Hsp90, instead the acetylation of Hsp70 was increased and Bcr-Abl was increasingly associated with Hsp70 rather than Hsp90, forming an unstable complex that promotes Bcr-Abl degradation. These results indicated that FK228 may disrupt the function of Hsp90 indirectly through acetylation of Hsp70 and inhibition of its function. 相似文献
17.
Marchion DC Bicaku E Daud AI Richon V Sullivan DM Munster PN 《Journal of cellular biochemistry》2004,92(2):223-237
Acetylation of histones leads to conformational changes of DNA. We have previously shown that the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induced cell cycle arrest, differentiation, and apoptosis. In addition to their antitumor effects as single agents, HDAC inhibitors may cause conformational changes in the chromatin, rendering the DNA more vulnerable to DNA damaging agents. We examined the effects of SAHA on cell death induced by topo II inhibitors in breast cancer cell lines. Topo II inhibitors stabilize the topo II-DNA complex, resulting in DNA damage. Treatment of cells with SAHA promoted chromatin decondensation associated with increased nuclear concentration and DNA binding of the topo II inhibitor and subsequent potentiation of DNA damage. While SAHA-induced histone hyperacetylation occurred as early as 4 h, chromatin decondensation was most profound at 48 h. SAHA-induced potentiation of topo II inhibitors was sequence-specific. Pre-exposure of cells to SAHA for 48 h was synergistic, whereas shorter pre-exposure periods abrogated synergy and exposure of cells to SAHA after the topo II inhibitor resulted in antagonistic effects. Synergy was not observed in cells with depleted topo II levels. These effects were not limited to specific types of topo II inhibitors. We propose that SAHA significantly potentiates the DNA damage induced by topo II inhibitors; however, synergy is dependent on the sequence of drug administration and the expression of the target. These findings may impact the clinical development of combining HDAC inhibitors with DNA damaging agents. 相似文献
18.
Batovska DI Kim DH Mitsuhashi S Cho YS Kwon HJ Ubukata M 《Bioscience, biotechnology, and biochemistry》2008,72(10):2623-2631
Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. 相似文献
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Di Wang Ming Zhao Guozhu Chen Xiang Cheng Xiaoxi Han Song Lin Xuhui Zhang Xiaodan Yu 《Apoptosis : an international journal on programmed cell death》2013,18(11):1348-1362
Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects. 相似文献
20.
The FDA-approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat) was modified to improve its selectivity for a single histone deaetylase (HDAC) isoform. We show that attaching an ethyl group at the C3 position transforms SAHA from nonselective to an HDAC6-selective inhibitor. Theses results indicate that small structural changes in SAHA can significantly influence selectivity, which will lead future anti-cancer design efforts targeting HDAC proteins. 相似文献