Synthesis and Histone Deacetylase Inhibitory Activity of New Benzamide Derivatives

Suzuki, Tateyuki; Ando, Tomoyuki; Tsuchiya, Katsumi; Fukazawa, Nobuyuki; Saito, Akiko; Mariko, Yukiyasu; Yamashita, Takashi; Nakanishi, Osamu

doi:10.1021/jm980565u

Cited by 274 publications

(209 citation statements)

References 6 publications

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“…Dose-response experiments (not shown) revealed that 22 and 23 possess IC50 values of 4.9 and 3.8 µM, respectively, which compares favorably to the IC 50 value of 4.8 µM reported for 2. 3 Compounds 9-18, 20, and 22 were next evaluated for their ability to promote in vitro reexpression of the cyclin-dependent kinase inhibitor p21 Waf1 , in cultured HCT116 human colon carcinoma cells, as shown in Table 2. These analogues were also assayed for their ability to promote increased acetylated histones H3 and H4 (AcH3, AcH4) and acetylated Rtubulin (AcTubulin).…”

Section: Biological Evaluationmentioning

confidence: 99%

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

et al. 2008

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A series of polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) were synthesized and evaluated as isoform-selective histone deacetylase (HDAC) inhibitors. These analogues contain a polyamine chain to increase affinity for chromatin and facilitate cellular import. Seven PAHAs inhibited HDAC >50% (1 µM), and two PABAs inhibited HDAC >50% (5 µM). Compound 17 increased acetylated α-tubulin in HCT116 colon tumor cells 253-fold but only modestly increased p21 waf1 and acetylated histones 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21 waf1 and acetylated histones 3 and 4 but caused dose-dependent increases in p21 waf1 in combination with 0.1 µM 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 µM. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.

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Section: Biological Evaluationmentioning

confidence: 99%

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

et al. 2008

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“…The advantage of this compound is that it has better physicochemical properties than TSA. 61,62 MS-275 promotes gene expression favoring growth arrest and differentiation with significantly increased expression of anti-proliferative genes such as p21 WAF1/CIP1 and the transforming growth factor (TGF)-β II receptor, and it also induced the maturation marker gelsolin. 63 CI-994 has shown efficacy in tumor-bearing mice but did not inhibit HDAC activity directly.…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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The epigenome of cancer cells is determined by DNA methylation and an array of post-translational modifications of the core histones. Epigenetic abnormalities are commonly found in human tumors and importantly, they can be reversed by pharmacologic inhibitors. Histone deacetylase inhibitors (HDACIs) represent one of the most promising epigenetic treatments for cancer. HDACIs have emerged as promising targets for cancer therapy because they reactivate the transcription of multiple genes that are silenced in human tumors and they show pleiotropic anti-tumor effects selectively in cancer cells. HDACIs are well-tolerated and several show promising anti-tumor activity. While gene transcription has been considered to be the major target of HDACIs, inhibition of acetylation of non-histone proteins is now emerging as a novel basis for their anti-tumor effects. In this review, we discuss new insights into the molecular mechanism of HDACIs, their current status of clinical development, and possible future uses in cancer therapy.

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“…21 Like many inhibitors using hydroxamate as the zinc-binding moiety, SAHA is not selective among different HDACs. In comparison, HDACs inhibitors containing an aminobenzamide as the zinc-binding group, such as MS-275 (SNDX-275), 22 MGCD0103 23 and Chidamide 24 ( Fig. 1), generally have less HDAC inhibitory activity but with higher class I selectivity.…”

Section: -20mentioning

confidence: 99%

Synthesis and Biological Evaluation of N-(Aminopyridine) Benzamide Analogues as Histone Deacetylase Inhibitors

Zhang¹,

Li²

2012

Bulletin of the Korean Chemical Society

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A series of benzamide-based histone deacetylases (HDACs) inhibitors possessing N-(aminopyridine) residue as the zinc binding site of HDAC were synthesized and evaluated. Among these derivatives, compounds with N-(2-amino-4-pyridine) benzamide moiety have been found as the most potent ones. Moreover, introduction of appropriate substituents on the terminal aryl group acting as the surface-recognition domain could significantly improve the antiproliferative activity. In particular, the compound 4k possessed favorable pharmacokinetic characteristics and exhibited potent antitumor activity on xenograft model in mice at well tolerated doses, thus suggesting a good therapeutic index.

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Synthesis and Histone Deacetylase Inhibitory Activity of New Benzamide Derivatives

Cited by 274 publications

References 6 publications

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Histone Deacetylase Inhibitors for Cancer Therapy

Synthesis and Biological Evaluation of N-(Aminopyridine) Benzamide Analogues as Histone Deacetylase Inhibitors

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