title: Design, synthesis, and biological evaluation of simplified side chain hybrids of the potent actin binding polyketides rhizopodin and bistramide.
abstract: 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.
authors: Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn (Germany).
authors: Daniel
authors: D
authors: Herkommer
authors: Sandra
authors: S
authors: Dreisigacker
authors: Galina
authors: G
authors: Sergeev
authors: Florenz
authors: F
authors: Sasse
authors: Holger
authors: H
authors: Gohlke
authors: Dirk
authors: D
authors: Menche
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004988:Ethers, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D061065:Polyketides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D018942:Macrolides; D010080:Oxazoles; D061065:Polyketides; C081739:rhizopodin
keywords: actin; analogues; bistramide; polyketides; rhizopodin