A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs
| Autor: | Frederick A. Valeriote, Yogan Khatri, Halina Pietraszkiewicz, David H. Sherman, Scott I Brody, Jennifer J. Schmidt, Catherine Zhu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Epoxide Antineoplastic Agents 01 natural sciences Biochemistry Article Mixed Function Oxygenases 03 medical and health sciences chemistry.chemical_compound Thioesterase Cell Line Tumor Depsipeptides Drug Discovery Humans chemistry.chemical_classification Depsipeptide 010405 organic chemistry General Medicine Combinatorial chemistry 0104 chemical sciences 030104 developmental biology Enzyme Drug development chemistry Cryptophycin Cyclization Benzyl group Molecular Medicine Thiolester Hydrolases Drug Screening Assays Antitumor Cryptophycins |
| Zdroj: | ACS Chem Biol |
| Popis: | The cryptophycins are a family of macrocyclic depsipeptide natural products that display exceptionally potent anti-proliferative activity against drug-resistant cancers. Unique challenges facing the synthesis and derivatization of this complex group of molecules motivated us to investigate a chemoenzymatic synthesis designed to access new analogs for biological evaluation. The cryptophycin thioesterase (CrpTE) and the cryptophycin epoxidase (CrpE) are a versatile set of enzymes that catalyze macrocyclization and epoxidation of over twenty natural cryptophycin metabolites. Thus, we envisioned a drug development strategy involving their use as standalone biocatalysts for production of unnatural derivatives. Herein, we developed a scalable synthesis of 12 new unit A-B-C-D linear chain elongation intermediates containing heterocyclic aromatic groups as alternatives to the native unit A benzyl group. N-acetyl cysteamine activated forms of each intermediate were assessed for conversion to macrocyclic products using wild type CrpTE, which demonstrated the exceptional flexibility of this enzyme. Semi-preparative scale reactions were conducted for isolation and structural characterization of new cryptophycins. Each was then evaluated as a substrate for CrpE P450 and its ability to generate the epoxidized products from these substrates that possess altered electronics at the unit A styrenyl double bond position. Finally, biological evaluation of the new cryptophycins revealed a des-β-epoxy analog with low picomolar potency, previously limited to cryptophycins bearing epoxide functionality. |
| Databáze: | OpenAIRE |
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