Design, Synthesis, and Biological Evaluation of Simplified Side Chain Hybrids of the Potent Actin Binding Polyketides Rhizopodin and Bistramide

• Published in: ChemMedChem 2015-03, Vol.10 (3), p.470-489
• Main Authors: Herkommer, Daniel, Dreisigacker, Sandra, Sergeev, Galina, Sasse, Florenz, Gohlke, Holger, Menche, Dirk
• Format: Article
• Language: English
• Subjects: actin; Actins - antagonists & inhibitors; Actins - chemistry; Actins - metabolism; analogues; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bistramide; Cell Line; Cell Proliferation - drug effects; Cytoskeleton; Drug Design; Ethers, Cyclic - chemistry; Ethers, Cyclic - pharmacology; Humans; Macrolides - chemistry; Macrolides - pharmacology; Molecular Docking Simulation; Oxazoles - chemistry; Oxazoles - pharmacology; polyketides; Polyketides - chemistry; Polyketides - pharmacology; rhizopodin; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402508

The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low‐nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G‐actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure–activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin–inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin–bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin–bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties. Less talk, more actin: X‐ray‐structure‐based in silico studies of the noncovalent interactions between complex polyketides and their natural target actin resulted in the design, modular synthesis, and biological evaluation of a novel and structurally simplified analogue class based on a hybrid structure of bistramide A and rhizopodin.