Identification and optimisation of a series of substituted 5-pyridin-2-yl-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

Price, Steve; Bordogna, Walter; Braganza, Ruth; Bull, Richard J.; Dyke, Hazel J.; Gardan, Sophie; Gill, Matthew; Harris, Neil V.; Heald, Robert A.; Heuvel, Marco van den; Lockey, Peter; Lloyd, Julia; Molina, Aránzazu García; Roach, A. G.; Roussel, Fabien; Sutton, J. Mark; White, Anne B.

doi:10.1016/j.bmcl.2006.10.045

Cited by 25 publications

(8 citation statements)

References 7 publications

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“…The antiproliferative activities of gold-2a in MDA-MB-231 cells were comparable with other HDACi, such as SAHA (43) and TSA (44). Previous studies have suggested that cisplatin and gold (III) porphyrin complexes elicit their anticancer effects through distinct mechanisms at the DNA level and the protein level, respectively (45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 72%

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

et al. 2010

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Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC 50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling.

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Section: Discussionmentioning

confidence: 72%

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

et al. 2010

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“…The laboratory tests utilized in identifying HDACIs are: HDAC from human leukemia K562 cells, purified recombinant human histone deacetylase (HDAC‐1), human colon cancer HCT 116 cells, human T‐24 cancer cells, HT1080 proliferation, partially purified human HDAC‐1, maize histone deacetylase (maize‐HD‐2), HDAC fluorescence activity/assay/drug discovery kit (AK‐500, Biomol Research Laboratories, Plymouth Meeting, PA) Friend leukemic cells, predominantly HDAC 1 and HDAC 2, human HT1080 fibrosarcoma cell line, mixture of HDAC‐1 and HDAC‐2 prepared from nuclear extraction of K562 erythroleukemia cells, HCT116 human colon, HD1‐A (homolog of mammalian class IIa HDACs), HD1‐B (homolog of mammalian class I HDAC), human lung cancer (A549) and breast cancer (SK‐BR‐3), H4‐Ac, HT1080 fibrosarcoma cells, purified HDAC 1, HDAC class II (HD1‐A), maize HDAC class I (HD1‐B), HeLa cell nuclear extract, H661 cell lines and HDAC 6. All the activity data have been collected from the literature 55, 102, 124–128, 130–132, 134–138, 146–149, 151, 156, 159, 160, 168, 169, 173, 174, 180, 181, 188–194, 196–199. The activity is expressed in molar concentration.…”

Section: Evaluation Of New Qsar Models—materials and Methodsmentioning

confidence: 99%

Histone deacetylase inhibitors (HDACIs). Structure—activity relationships: history and new QSAR perspectives

Pontiki

Hadjipavlou‐Litina

2011

Medicinal Research Reviews

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Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. HDAC inhibitors (HDACIs) block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumor cells. In this article, a survey of published quantitative structure-activity relationships (QSARs) studies are presented and discussed in the hope of identifying the structural determinants for anticancer activity. Secondly a two-dimensional QSAR study was carried out on biological results derived from various types of HDACIs and from different assays using the C-QSAR program of Biobyte. The QSAR analysis presented here is an attempt to organize the knowledge on the HDACIs with the purpose of designing new chemical entities with enhanced inhibitory potencies and to study the mechanism of action of the compounds. This study revealed that lipophilicity is one of the most important determinants of activity. Additionally, steric factors such as the overall molar refractivity (CMR), molar volume (MgVol), the substituent's molar refractivity (MR) (linear or parabola), or the sterimol parameters B(1) and L are important. Electronic parameters indicated as σ(p), are found to be present only in one case.

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“…[7] investigated a series of thienyl-based hydroxamic acids[7] that include ADS100380 and ADS102550, which led to the identification of the 5-pyridin-2-yl-thiophene-2-hydroxamic acid, possessed modest HDAC inhibitory activity.…”

Section: Hydroxamic Acid As Anticancermentioning

confidence: 99%

Hydroxamic acid - A novel molecule for anticancer therapy

Pal¹,

Saha²

2012

J Adv Pharm Technol Res

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Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.

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Identification and optimisation of a series of substituted 5-pyridin-2-yl-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

Cited by 25 publications

References 7 publications

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway

Histone deacetylase inhibitors (HDACIs). Structure—activity relationships: history and new QSAR perspectives

Hydroxamic acid - A novel molecule for anticancer therapy

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