Discovery of adamantane based highly potent HDAC inhibitors

Gopalan, Balasubramanian; Ponpandian, Thanasekaran; Kachhadia, V. V.; Bharathimohan, Kuppusamy; Radhakrishnan, Vignesh; Sivasudar, Velaiah; Narayanan, Shridhar; Mandar, Bhonde; Rajendran, Praveen; Saranya, N; Rajagopal, Sriram; Rajagopal, Sridharan

doi:10.1016/j.bmcl.2013.03.002

Cited by 39 publications

(17 citation statements)

References 41 publications

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“… 26 Further, adamantane-based hydroxamic acids were recently reported and showed strong evidence of HDAC inhibition. 27 Using these previous studies to guide our synthesis efforts, we designed compound 6 , a cinnamic acid-based HDAC inhibitor containing an adamantyl group as a ‘blood brain barrier (BBB) carrier’ (Figure 1 ). Compound 6 was synthesized through reductive amination, followed by conversion into a hydroxamic acid in the presence of hydroxylamine and sodium hydroxide.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

et al. 2014

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Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [11C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [11C]6 for human epigenetic imaging.

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Section: Resultsmentioning

confidence: 99%

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

et al. 2014

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“…Compounds utilizing novel chemical scaffolds such as adamantane and noradamantane have been shown to inhibit HDACs at picomolar concentrations, and to inhibit tumor cell growth with limited toxicities in vivo at low nanomolar ranges (91). Chemical hybrid molecules containing both HDACi activity and an additional anticancer module are under development, and while the HDACi component is relatively broad spectrum, targeting HDACs concurrent with inhibition of PI3K (CUDC-907), tyrosine kinase (CUDC-101), or topoisomerase II (daunorubicin-vorinostat), or with 1α,25-vitamin D (triciferol) for nuclear receptor targeting (92), may be of interest for particular cancer subtypes.…”

Section: Hybrid Molecules Targeting Hdacs and Other Oncogenic Proteinmentioning

confidence: 99%

New and emerging HDAC inhibitors for cancer treatment

West¹,

Johnstone²

2014

J. Clin. Invest.

1,175

1,105

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Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

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“…Interestingly, in a recent paper from Gopalan et al [13], adamantyl-based HDAC inhibitors were found to exhibit cytotoxicity in the nanomolar range.…”

Section: Chartmentioning

confidence: 99%

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

Cincinelli¹,

Musso²,

Giannini³

et al. 2014

European Journal of Medicinal Chemistry

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To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116.

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Discovery of adamantane based highly potent HDAC inhibitors

Cited by 39 publications

References 41 publications

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

New and emerging HDAC inhibitors for cancer treatment

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

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