- 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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- 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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- 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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