A Modular Approach to Build Macrocyclic Diversity in Aminoindoline Scaffolds Identifies Antiangiogenesis Agents from a Zebrafish Assay

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

doi:10.1002/ejoc.201300409

Cited by 12 publications

(6 citation statements)

References 39 publications

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“…Hence, simple substituted benzene, carbazole, indole, benzo[b]thiophene and 1,1 0 -binaphthyl (68) macrocycles have been synthesized using RCM. 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''.…”

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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Section: Ring-closing Metathesismentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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“…Angiogenesis is a hallmark behaviour of cancer that can be easily interrogated through phenotypic screens in zebrafish embryos. The groups of Arya and Kitambi have made a systematic study of the preparation of DOS libraries of macrocycles and their assessment as anti-angiogenic agents [44,45,46,47]. The choice of macrocyclic scaffolds was driven by their ubiquity in bioactive natural products, including those able to modulate protein-protein interactions, and by the relative paucity of this scaffold type in medicinal chemistry approaches [48].…”

Section: Dos As a Source Of New Chemical Tools For Cancer Biologymentioning

confidence: 99%

“…A similar amide coupling and RCM strategy was applied to stereochemically diverse carbohydrate-derived stereo-tetrads to prepare 14-membered glycohybrid macrocycles, e.g., 27 [44]. Ring closing metathesis was also the key step in the construction of a 39-membered library of macrocycles based on the tri-functional aminoindoline 25 [47]. Here, the additional substitution points on the core allowed for the formation of fused or bridged macrocycles.…”

Section: Dos As a Source Of New Chemical Tools For Cancer Biologymentioning

confidence: 99%

Diversity-Oriented Synthetic Strategies Applied to Cancer Chemical Biology and Drug Discovery

Collins

Jones

2014

Molecules

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How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery.

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“…[6,[8][9][10][11][12][13] One of the major reasons is the lack of a wide variety of efficient synthesis methods to allow access to these compounds and their structurally related analogs in an efficient manner. [6,[8][9][10][11][12][13] One of the major reasons is the lack of a wide variety of efficient synthesis methods to allow access to these compounds and their structurally related analogs in an efficient manner.…”

Section: Introductionmentioning

confidence: 99%

An Intramolecular Heck Approach To Obtain 17‐Membered Macrocyclic Diversity and the Identification of an Antiangiogenesis Agent from a Zebrafish Assay

et al. 2013

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We report a practical and modular approach to obtain two different types of 17‐membered ring macrocyclic compounds through an intramolecular Heck reaction. These macrocyclic compounds are functionalized, that is, they contain two contiguous stereogenic hydroxy functional groups and an amino acid moiety in the macrocyclic ring skeleton. The macrocycles were then screened against a zebrafish assay to determine the antiangiogenesis activity of these small molecules. Macrocyclic compound 2.2a was identified as a potent inhibitor at 2.5 μM, whereas its acyclic precursor and the other related macrocyclic compounds did not show any effect.

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A Modular Approach to Build Macrocyclic Diversity in Aminoindoline Scaffolds Identifies Antiangiogenesis Agents from a Zebrafish Assay

Cited by 12 publications

References 39 publications

The Synthesis of Macrocycles for Drug Discovery

The Synthesis of Macrocycles for Drug Discovery

Diversity-Oriented Synthetic Strategies Applied to Cancer Chemical Biology and Drug Discovery

An Intramolecular Heck Approach To Obtain 17‐Membered Macrocyclic Diversity and the Identification of an Antiangiogenesis Agent from a Zebrafish Assay

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