Tetrahydroquinoline-Derived Macrocyclic Toolbox: The Discovery of Antiangiogenesis Agents in Zebrafish Assay

Guduru, Shiva Krishna Reddy; Chamakuri, Srinivas; Chandrasekar, Gayathri; Kitambi, Satish Srinivas; Arya, Prabhat

doi:10.1021/ml400026n

Cited by 13 publications

(4 citation statements)

References 39 publications

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“…The removal of an Fmoc protecting group prior to an aza-Michael addition has been reported , as well as the aza-Michael of an amide nitrogen to an acrylate preactivated with TBSOTf . There are also examples of direct acid catalysis without preactivation when the attacking nucleophile is an aniline nitrogen as well as base promoted aza-Michael of Cbz protected nitrogen. − For the “inter” route there are limited examples of ethanolamine, either directly or as a synthon, being used as an aza-Michael donor. − Closure of a piperazine ring from β-hydroxyamine precursors has generally been carried out by either halogenation, mesylate displacement , or with the Mitsunobu protocol. − None of these precedents had been applied toward the production of complete stereoisomeric matrices of 2,3-piperazine products.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

et al. 2018

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The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 → 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

et al. 2018

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“…166 Using RCM as the enabling chemistry, Arya and co-workers have reported on an impressively diverse collection of 12-to 15-membered macrocycles that exhibit activity as inhibitors of angiogenesis and early embryonic development, including glycohybrids (69, Figure 11.9), 167 benzo-fused analogues (70), 168 C-linked carbohydrate derivatives (71), 169 aminoindolines (72) 170 and tetrahydroquinolines (73). 171 RCM also is one of the primary methods utilized to create conformationally fixed helical peptide macrocycles, often termed ''stapled peptides''. [172][173][174][175] The first compound of this type, ALRN-5281 (not shown), 176 a growth hormone-releasing hormone agonist 177 for treating growth hormone deficiency and HIV lipodystrophy, has recently completed its first clinic trial.…”

Section: Ring-closing Metathesismentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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“…The enantiopure 2,6- cis -tetrahydropyran moiety ( 22 ) was hydrolyzed with LiOH to obtain the carboxylic acid, which was then coupled with four secondary amines 24 (Scheme ) using EDC·HCl and HOBT as the coupling reagents to obtain 23 . The synthesis details (with R 1 as the first diversity site) are provided in the Supporting Information.…”

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confidence: 99%

Stereoselective Synthesis of Rapamycin Fragment To Build a Macrocyclic Toolbox

et al. 2015

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A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective β-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction. The other piece needed for building the macrocyclic diversity was obtained from the coupling of various amino alcohol moieties with S-pipecolic acid.

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Tetrahydroquinoline-Derived Macrocyclic Toolbox: The Discovery of Antiangiogenesis Agents in Zebrafish Assay

Cited by 13 publications

References 39 publications

Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

The Synthesis of Macrocycles for Drug Discovery

Stereoselective Synthesis of Rapamycin Fragment To Build a Macrocyclic Toolbox

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