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

Abstract

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.

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

“…As an extension of this work, with the objective to explore macrocyclic chemical space, [26,27] we report herein a modular method that allowed us to incorporate different types of medium/large ring skeletons (see 1.2, 1.3, and 1.4; Scheme 1) into enantioenriched aminoindoline scaffold 1.1. There are several attractive features of aminoindoline scaffold 1.1 that make it an attractive starting point to incorporate various medium/large rings into the skeleton.…”

The Synthesis of Macrocycles for Drug Discovery

“…202 a key intermediate for the synthesis of HCV protease inhibitors (98, Figure 11 Scheme 11.10 Heck routes to macrocycles.…”

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

“…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].…”

“…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]. The bi-functional building blocks 24 and ent- 24 (Scheme 9), accessed through Sharpless asymmetric epoxidation, were elaborated by amide couplings and macrocyclised either through intramolecular Heck coupling or by RCM to give 17- or 14-member rings, respectively [45,46]. Varying the order of introduction of the building blocks allowed for scaffold variation in each case, and replacement of the alkylamine or nitro groups of 24 by hydroxyl groups gave further diversity.…”