Total Synthesis of Azumamide A and Azumamide E, Evaluation as Histone Deacetylase Inhibitors, and Design of a More Potent Analogue

Wen, Shulin; Carey, Krystle L.; Nakao, Yoichi; Fusetani, Nobuhiro; Packham, Graham; Ganesan, A.

doi:10.1021/ol070046y

Cited by 52 publications

(55 citation statements)

References 14 publications

(11 reference statements)

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“…Several academic groups have accomplished the total synthesis of the azumamides. In Ganesan's route, 84 the unnatural b-amino acid was prepared by an imino aldol reaction between imine 55 (Scheme 4.5) containing Ellman's tert-butylsulfinyl chiral auxiliary 85 and a propionate enolate to afford 56 as a single diastereomer. This was carried forward to a linear peptide followed by macrolactamization to accomplish the total synthesis of azumamides A and E. Biological assays established that azumamide A (HeLa HDACs IC 50 ¼ 5800 nM) was a significantly poorer HDAC inhibitor compared to azumamide E (HeLa HDACs IC 50 ¼ 110 nM), as would be predicted based on the weaker zinc binding affinity of a neutral carboxamide relative to an ionized carboxylic acid.…”

Section: The Azumamide Natural Products With a Carboxylic Acid Warheadmentioning

confidence: 99%

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Ganesan

2014

Macrocycles in Drug Discovery

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The modulation of epigenetic targets has recently become an attractive strategy for drug discovery. Among these, it is the inhibition of histone deacetylases (HDACs) that has received the most attention. Numerous HDAC inhibitors have advanced to clinical trials and two have received FDA approval as anticancer agents. This chapter reviews natural and synthetic inhibitors of zinc-dependent HDACs that contain a macrocyclic scaffold including the trapoxin and apicidin cyclic tetrapeptides, the FK228 depsipeptide family, the azumamides and fully synthetic macrocycles.

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Section: The Azumamide Natural Products With a Carboxylic Acid Warheadmentioning

confidence: 99%

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Ganesan

2014

Macrocycles in Drug Discovery

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“…A synthetic hydroxamic acid derivative of Azumamide E (Fig. (5), compound 59) was reported to have IC 50 = 0.007 μM in nuclear extracts from HeLa cells [101].…”

Section: Cyclic Peptidesmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Moradei¹,

Vaisburg²,

Martell³

2008

CTMC

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Histone deacetylase (HDAC) inhibitors constitute a novel and growing class of anticancer agents that function by altering intracellular patterns of histone acetylation, the so-called epigenetic "histone code," thereby producing changes in cell cycle arrest, differentiation, and/or apoptosis in tumor cells. This overview describes the chemistry and preliminary characterization of recently disclosed molecules in three major classes of HDAC inhibitors: hydroxamic acids, 2-amino- benzanilides, and cyclic peptides. In addition, results from recent clinical trials on isotype-selective HDAC inhibitors are reviewed. It is clear from the plethora of new molecules and the encouraging results from clinical trials that HDAC inhibitors hold a great deal of promise, particularly as add-on therapy, for the treatment of a variety of solid and hematologic cancers.

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“…When isolated from the marine sponge little difference in activity was seen between azumamides A and E, the amide and carboxylic acid respectively. However, when a synthetic sample of each was prepared subtle differences were observed [78]. While the synthetic sample of azumamide A inhibited HDAC nuclear extracts from HeLa cells with IC 50 = 5.8 μM, the corresponding carboxylic acid azumamides E showed IC 50 = 110 nM.…”

Section: Cyclic Tetrapeptide Natural Productsmentioning

confidence: 99%

From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents

Jones¹,

Steinkühler²

2008

CPD

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Histone deacetylases (HDACs) are one of two counteracting enzyme families whose activity controls the acetylation state of lysine protein residues, notably those contained in the N-terminal extensions of the core histones. Deregulation of the acetylation state of specific lysine residues has been implicated in a multitude of biologic processes, notably cancer, where HDACs are known to be involved in the control of cell cycle progression, cell survival and differentiation. HDAC inhibitors are being developed as anti-neoplastic agents. Nature has led the way in the development of these compounds, with trichostatin A being the first hydroxamic acid HDAC inhibitor identified. Likewise, the disulfide depsipeptide Romidepsin is currently in clinical trials, while an array of cyclic tetrapeptides HDAC inhibitors have been reported. Rational drug design has allowed these cyclic tetrapeptide to be transformed into equally potent small molecule inhibitors selective for either class I or class II HDACs. While acyclic alkyl ketones have been demonstrated to be selective HDAC 1, 2 and 3 inhibitors with efficacy in xenograft models, trifluoromethyl ketones have been shown to be selective inhibitors for class II HDACs and recently have been revealed to bind in the active site of the enzyme in their hydrated form.

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Total Synthesis of Azumamide A and Azumamide E, Evaluation as Histone Deacetylase Inhibitors, and Design of a More Potent Analogue

Cited by 52 publications

References 14 publications

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents

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