InChI=1S/C16H25N3O3/c1- 19(2)14-10-8-13(9-11-14)16(21)17-12-6-4-3-5-7-15(20)18-22/h8-11,22H,3-7,12H2,1-2H3,(H,17,21)(H,18,20) |
| MXWDSZWTBOCWBK-UHFFFAOYSA-N |
| CN(C)C1=CC=C(C=C1)C(=O)NCCCCCCC(=O)NO |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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apoptosis inducer
Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms.
EC 3.5.1.98 (histone deacetylase) inhibitor
An EC 3.5.1.* (non-peptide linear amide C-N hydrolase) inhibitor that interferes with the function of histone deacetylase (EC 3.5.1.98).
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
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Outgoing
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4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
has role
antineoplastic agent
(CHEBI:35610)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
has role
apoptosis inducer
(CHEBI:68495)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
has role
EC 3.5.1.98 (histone deacetylase) inhibitor
(CHEBI:61115)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
is a
benzamides
(CHEBI:22702)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
is a
hydroxamic acid
(CHEBI:24650)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
is a
secondary carboxamide
(CHEBI:140325)
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
(CHEBI:125562)
is a
tertiary amino compound
(CHEBI:50996)
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4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
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4-dimethylamino-N-(6-hydroxycarbamoylhexyl)benzamide
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ChEBI
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D237
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ChEBI
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histone deacetylase inhibitor III
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ChEBI
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M-344
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LINCS
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M344
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ChEBI
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N-hydroxy-7-(4-dimethylaminobenzoyl)aminoheptanamide
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ChEBI
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8570090
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Reaxys Registry Number
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Reaxys
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Jin L, Guo Q, Zhu HY, Xing XX, Zhang GL, Xuan MF, Luo QR, Luo ZB, Wang JX, Choe HM, Paek HJ, Yin XJ, Kang JD (2017)
Histone deacetylase inhibitor M344 significantly improves nuclear reprogramming, blastocyst quality, and in vitro developmental capacity of cloned pig embryos.
Journal of animal science 95, 1388-1395 [PubMed:28380503]
[show Abstract]
M344 is a novel histone deacetylase inhibitor. There is no report on the effect of M344 treatment on the development of pig embryos after somatic cell nuclear transfer (SCNT). In the present study, we investigated the effect of M344 on the blastocyst formation rate in cloned embryos, acetylation level of histone H4 lysine 12 (AcH4K12), and the expression of pluripotency-related genes , , and . Our results indicated that treatment with 5 µ M344 for 6 h improved the development of porcine embryos, in comparison with the untreated group (25.1% ± 5.0 vs. 10.9% ± 2.4; < 0.05). Moreover, M344-treated embryos had increased average fluorescence intensity of AcH4K12 at the pseudo-pronuclear stage ( < 0.05). However, no differences exist in Oct4, NANOG, and SOX2 expression in M344-treated and untreated SCNT blastocysts. In evaluating the effect of M344 on in vivo development, 845 M344-treated embryos were transferred into 3 surrogates, 1 of whom became pregnant and developed 3 fetuses. These findings suggested that M344 elevated the level of histone acetylation, facilitated the nuclear programming, and subsequently improved the developmental competence of pig SCNT embryos. | Volmar CH, Salah-Uddin H, Janczura KJ, Halley P, Lambert G, Wodrich A, Manoah S, Patel NH, Sartor GC, Mehta N, Miles NTH, Desse S, Dorcius D, Cameron MD, Brothers SP, Wahlestedt C (2017)
M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory.
Proceedings of the National Academy of Sciences of the United States of America 114, E9135-E9144 [PubMed:29073110]
[show Abstract]
Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression. M344 increases the expression of AD-relevant genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65, both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L) mice with M344, at doses as low as 3 mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation, novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief pulses of daily drug treatment may be sufficient for long-term efficacy. Together, these data show that M344 normalizes several disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be used to address the polygenic nature of multifactorial diseases. | (2013)
Retraction notice to "M344 is a novel synthesized histone deacetylase inhibitor that induces growth inhibition, cell cycle arrest, and apoptosis in human endometrial cancer and ovarian cancer cells" [Gynecol. Oncol. 101 (2006) 108-113].
Gynecologic oncology 129, 270 [PubMed:23638461] | Yeung A, Bhargava RK, Ahn R, Bahna S, Kang NH, Lacoul A, Niles LP (2012)
HDAC inhibitor M344 suppresses MCF-7 breast cancer cell proliferation.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 66, 232-236 [PubMed:22436652]
[show Abstract]
Histone deacetylase (HDAC) inhibitors represent a novel class of drugs that selectively induce cell cycle arrest and apoptosis in transformed cells. This study examined, for the first time, the effects of the relatively new HDAC inhibitor, M344 [4-dimethylamino-N-(6-hydroxycarbamoylhexyl)-benzamide], on the proliferation of MCF-7 breast cancer cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed significant concentration- and time-dependent decreases in MCF-7 cell proliferation following treatment with M344 (1-100μM). In contrast to the significant induction of p21(waf1/cip1) mRNA expression following treatment with M344 (10μM) for 1 or 3 days, there was a significant decrease in p53 mRNA expression, although p53 protein levels were unchanged. Similar treatment with M344 also induced expression of the pro-apoptotic genes, Puma and Bax, together with the morphological features of apoptosis, in MCF-7 cells. The results of this study reinforce previous findings indicating that HDAC inhibitors are an important group of oncostatic drugs, and show that M344 is a potent suppressor of breast cancer cell proliferation. | Weberpals JI, O'Brien AM, Niknejad N, Garbuio KD, Clark-Knowles KV, Dimitroulakos J (2011)
The effect of the histone deacetylase inhibitor M344 on BRCA1 expression in breast and ovarian cancer cells.
Cancer cell international 11, 29 [PubMed:21854619]
[show Abstract]
BackgroundThe inhibition of Breast Cancer 1 (BRCA1) expression sensitizes breast and ovarian cancer cells to platinum chemotherapy. However, therapeutically relevant agents that target BRCA1 expression have not been identified. Our recent report suggested the potential of the histone deacetylase (HDAC) inhibitor, M344, to inhibit BRCA1 expression. In this study, we further evaluated the effect of M344 on BRCA1 mRNA and protein expression, as well as its effect on cisplatin-induced cytotoxicity in various breast (MCF7, T-47D and HCC1937) and ovarian (A2780s, A2780cp and OVCAR-4) cancer cell lines.ResultsWith the addition of M344, the platinum-sensitive breast and ovarian cancer cell lines that displayed relatively high BRCA1 protein levels demonstrated significant potentiation of cisplatin cytotoxicity in association with a reduction of BRCA1 protein. The cisplatin-resistant cell lines, T-47D and A2780s, elicited increased cytotoxicity of cisplatin with M344 and down regulation of BRCA1 protein levels. A2780s cells subjected to combination platinum and M344 treatment, demonstrated increased DNA damage as assessed by the presence of phosphorylated H2A.X foci in comparison to either treatment alone. Using Chromatin Immunoprecipitation, A2780s and MCF7 cells exposed to M344 alone and in combination with cisplatin, did not demonstrate enhanced acetylated Histone 4 at the BRCA1 promoter, suggesting an indirect effect on this promoter.ConclusionsThe enhanced sensitivity of HDAC inhibition to platinum may be mediated through a BRCA1-dependent mechanism in breast and ovarian cancer cells. The findings of this study may be important in the future design of clinical trials involving HDAC inhibitors using BRCA1 as a tumour biomarker. | St Germain C, O'Brien A, Dimitroulakos J (2010)
Activating Transcription Factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination.
Cancer cell international 10, 32 [PubMed:20828393]
[show Abstract]
BackgroundActivating Transcription Factor (ATF) 3 is a key regulator of the cellular integrated stress response whose expression has also been correlated with pro-apoptotic activities in tumour cell models. Combination treatments with chemotherapeutic drugs, such as cisplatin, and histone deacetylase (HDAC) inhibitors have been demonstrated to enhance tumour cell cytotoxicity. We recently demonstrated a role for ATF3 in regulating cisplatin-induced apoptosis and others have shown that HDAC inhibition can also induce cellular stress. In this study, we evaluated the role of ATF3 in regulating the co-operative cytotoxicity of cisplatin in combination with an HDAC inhibitor.ResultsThe HDAC inhibitor M344 induced ATF3 expression at the protein and mRNA level in a panel of human derived cancer cell lines as determined by Western blot and quantitative RT-PCR analyses. Combination treatment with M344 and cisplatin lead to increased induction of ATF3 compared with cisplatin alone. Utilizing the MTT cell viability assay, M344 treatments also enhanced the cytotoxic effects of cisplatin in these cancer cell lines. The mechanism of ATF3 induction by M344 was found to be independent of MAPKinase pathways and dependent on ATF4, a known regulator of ATF3 expression. ATF4 heterozygote (+/-) and knock out (-/-) mouse embryonic fibroblast (MEF) as well as chromatin immunoprecipitation (ChIP) assays were utilized in determining the mechanistic induction of ATF3 by M344. We also demonstrated that ATF3 regulates the enhanced cytotoxicity of M344 in combination with cisplatin as evidenced by attenuation of cytotoxicity in shRNAs targeting ATF3 expressing cells.ConclusionThis study identifies the pro-apoptotic factor, ATF3 as a novel target of M344, as well as a mediator of the co-operative effects of cisplatin and M344 induced tumour cell cytotoxicity. | Li X, Chen BD (2009)
Histone Deacetylase Inhibitor M344 Inhibits Cell Proliferation and Induces Apoptosis in Human THP-1 Leukemia Cells.
American journal of biomedical sciences 1, 352-363 [PubMed:20526416]
[show Abstract]
Histone acetylation plays an important role in the silencing and activation of genes involved in tumoregenesis. Trichostatin A, originally identified as an anti-fungal drug, is a potent inhibitor of histone deacetylase (HDAC) with potential anti-tumor activity. In this study, we investigated the effect of M344, an amide analogues of trichostatin A, on the growth and differentiation of THP-1 human leukemia cells. We showed that at low doses, (< 0.2 muM), M344 could inhibit the growth of THP-1 cells at G1 phase in vitro with low cytotoxic effect. Low dose of M344 exerted some differentiating effect on THP-1 cells as judged by the expression of c-fms proto-oncogene (M-CSF receptor) and appearance of adherent cells. Growth arrest induced by M344 is associated with increased levels of cyclin-dependent protein kinase inhibitor p21 and cyclin E, in agreement with G1 phase arrest. At higher doses (2 muM), M344 could induce THP-1 cells to undergo apoptosis, which was associated with the cleavage of PARP, cytochrome c release and activation of both caspases-8, -9, followed by the activation of caspase-3. In addition, M344 could increase the levels of pro-apoptotic protein Bax but decreased the levels of anti-apoptotic protein XIAP. M344 is a potent activator of NF-kappaB transcription factor. RT-PCR assay showed that the M344 could transiently increase IL-1 expression yet markedly decreased TNF-alpha expression. Our results show that M344 is a potent growth inhibitor and inducer of apoptosis in human leukemia cells and suggest potential therapeutic strategies of HDAC inhibitors for patients with leukemias. | Hölsken A, Eyüpoglu IY, Lueders M, Tränkle C, Dieckmann D, Buslei R, Hahnen E, Blümcke I, Siebzehnrübl FA (2006)
Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases.
Acta neuropathologica 112, 205-215 [PubMed:16773328]
[show Abstract]
Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concentrations of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compounds were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21(WAF1) were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric analysis. Considering the ability of MS-275 to cross the blood-brain barrier, our experimental model identifies the benzamide MS-275 as a promising therapeutic compound for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas. | Takai N, Ueda T, Nishida M, Nasu K, Narahara H (2006)
M344 is a novel synthesized histone deacetylase inhibitor that induces growth inhibition, cell cycle arrest, and apoptosis in human endometrial cancer and ovarian cancer cells.
Gynecologic oncology 101, 108-113 [PubMed:16263156]
[show Abstract]
ObjectiveHistone deacetylase inhibitors (HDACIs) can inhibit cell proliferation, induce cell cycle arrest, and stimulate apoptosis of cancer cells.MethodsWe investigated the effects of a novel synthesized HDACI, M344, on Ishikawa endometrial cancer cell line, SK-OV-3 ovarian cancer cell line, and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of M344, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated.Results3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of M344, although normal endometrial epithelial cells were viable after the treatment with the same doses of M344 that induced growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to M344 decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, M344 treatment of these cell lines increased acetylation of H3 and H4 histone tails.ConclusionsThese results raise the possibility that M344 may prove particularly effective in the treatment of endometrial cancers and ovarian cancers. | Riessland M, Brichta L, Hahnen E, Wirth B (2006)
The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells.
Human genetics 120, 101-110 [PubMed:16724231]
[show Abstract]
Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the number of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only approximately 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-beta1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs). Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total number of gems/nucleus as well as the number of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of Delta7-SMN2 into FL-SMN2 transcripts as demonstrated by quantitative RT-PCR is most likely facilitated by elevated levels of Htra2-beta1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concentrations. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA. | Remiszewski SW, Sambucetti LC, Atadja P, Bair KW, Cornell WD, Green MA, Howell KL, Jung M, Kwon P, Trogani N, Walker H (2002)
Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.
Journal of medicinal chemistry 45, 753-757 [PubMed:11831887]
[show Abstract]
Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21(waf1) (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially. | Jung M, Brosch G, Kölle D, Scherf H, Gerhäuser C, Loidl P (1999)
Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation.
Journal of medicinal chemistry 42, 4669-4679 [PubMed:10579829]
[show Abstract]
Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to their ability to modulate transcription and to induce apoptosis or differentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activities in the submicromolar range. Here we report structure-activity relationship analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differentiation in Friend leukemic cells. This is the first report that shows the correlation between HD inhibitory activity and action on cancer cells on a larger series of similar compounds. Only the compounds that inhibit HD induce differentiation and/or exert antiproliferative activities in cell culture. Our studies support the use of in vitro systems as screening tools and provide structure-activity relationships that merit further investigation of this interesting target. |
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