Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1.

We report the synthesis of four different types of macrocyclic‐derived glycohybrids from carbohydrates that have an amino acid moiety in the large‐ring skeleton. These macrocyclic glycohybrids were obtained from α‐C‐1H‐ and β‐C‐1H‐linked carbohydrates. In one series, we utilized ring‐closing metathesis as the “stitching technology” to obtain two different macrocycles, i.e., trans equatorial–axial C‐1H and C‐5H and cis axial–axial C‐1H and C‐5H. The click approach was the key reaction in our second series to obtain two other macrocyclic compounds, i.e., trans equatorial–axial C‐1H and C‐5H and cis axial–axial C‐1H and C‐5H. The evaluation of this toolbox resulted in the identification of two unique compounds as antiangiogenesis agents in an embryonic zebrafish assay. Interestingly, in both cases, the macrocyclic compounds that have a cis relationship (i.e., axial–axial orientation) between C‐1H and C‐5H showed activity and their other diastereomers (i.e., equatorial–axial C‐1H and C‐5 H) with a trans relationship did not show any effect.

A practical and modular approach to obtain a diverse set of 14-membered macrocyclic compounds from carbohydrates is developed that utilizes functional groups at C-1 and C-5. The evaluation of this toolbox in various zebrafish assays led to the identification of 2.7f as an antiangiogenesis agent.