- Design, synthesis, biological evaluation, and structural characterization of potent mistone deacarylase inhibitors based on cyclic α/β- tetrapeptide architectures
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Histone deacetylases (HDACs) are a family of enzymes found in bacteria, fungi, plants, and animals that profoundly affect cellular function by catalyzing the removal of acetyl groups from ε-N-acetylated lysine residues of various protein substrates including histones, transcription factors, α-tubulin, and nuclear importers. Although the precise roles of HDAC isoforms in cellular function are not yet completely understood, inhibition of HDAC activity has emerged as a promising approach forreversing the aberrant epigenetic states associated with cancer and oth er chronic diseases. Potent new isoform-selective HDAC inhibitors would therefore help expand our understanding of the HDAC enzymes and represent attractive lead compounds for drug design, especially if combined withhigh-resolution structural analyses of such inhibitors to shed light on the three-dimensional pharmacophoric features necessary for the future design of more potent and selective compounds. Here we present structura l and functional analyses of a series of β acid-containing HDAC inhibitors inspired by cyclic tetrapeptide natural products. To survey a diverse ensemble of pharmacophoric configurations, we systematically varied the position of the β-amino acid, amino acid chirality, functionalization of the Zn2+-coordinating amino acid side chain, and alkylation of the backbone amide nitrogen atoms around the macrocycle. In many cases, the compounds were a single conformation in solution and exhibited potent activities against a number of HDAC isoforms as well as effective antiproliferative and cytotoxic activities against human tumorcells. High-resolution NMR solution structures were determined for a se lection of the inhibitors, providing a useful means of correlating detailed structural information with potency. The structure-based approach described here is expected to furnish valuable insights toward the future design of more selective HDAC inhibitors.
- Montero, Ana,Beierle, John M.,Olsen, Christian A.,Ghadiri, M. Reza
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supporting information; experimental part
p. 3033 - 3041
(2009/09/04)
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- A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo
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Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy, and the first generation HDAC inhibitors are currently in the clinic. Entirely novel ketone HDAC inhibitors have been developed from the cyclic tetrapeptide apicidin. These compounds show class I subtype selectivity and levels of cellular activity comparable to clinical candidates. A representative example has demonstrated tumor growth inhibition in a human colon HCT-116 carcinoma xenograft model comparable to known inhibitors.
- Jones, Philip,Altamura, Sergio,De Francesco, Raffaele,Paz, Odalys Gonzalez,Kinzel, Olaf,Mesiti, Giuseppe,Monteagudo, Edith,Pescatore, Giovanna,Rowley, Michael,Verdirame, Maria,Steinkühler, Christian
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p. 2350 - 2353
(2008/12/22)
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- Ring-closing metathesis in the synthesis of biologically active peptidomimetics of apicidin A
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Syntheses of novel 16-membered macrocyclic peptidomimetics are reported, which employ iterative peptide coupling followed by high yielding ring-closing metathesis (RCM) as the key cyclization step. The target macrocyclic compounds include examples contain
- Deshmukh, Prashant H.,Schulz-Fademrecht, Carsten,Procopiou, Panayiotis A.,Vigushin, David A.,Coombes, R. Charles,Barrett, Anthony G. M.
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p. 175 - 183
(2008/02/03)
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- Efficient Syntheses of Biologically Important (S)-2-Amino-8-oxodecanoic Acid (Aoda) and Homologues
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The efficient and practical asymmetric syntheses of the biologically important (S)-2-amino-8-oxodecanoic ester and its homologues have been achieved employing the Schoellkopf chiral auxiliary. Carbon-carbon bond formation between the appropriate alkyl bromide and the LDA generated anion of the Schoellkopf auxiliary, followed by hydrolysis provided the desired methyl ester of a long-chained keto amino acid in high yield with high selectivity.
- Kim, Sanghee,Kim, Eun-Young,Ko, Hyojin,Jung, Young Hoon
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p. 2194 - 2198
(2007/10/03)
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