642087-20-5Relevant academic research and scientific papers
A versatile chemoenzymatic synthesis for the discovery of potent cryptophycin analogs
Brody, Scott I.,Khatri, Yogan,Pietraszkiewicz, Halina,Schmidt, Jennifer J.,Sherman, David H.,Valeriote, Frederick A.,Zhu, Catherine
, p. 524 - 532 (2020/03/11)
The cryptophycins are a family of macrocyclic depsipeptide natural products that display exceptionally potent antiproliferative 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 20 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. Semipreparative 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.
Efficient and versatile stereoselective synthesis of cryptophycins
Mast, Christian Alexander,Eissler, Stefan,Stoncius, Arvydas,Stammler, Hans-Georg,Neumann, Beate,Sewald, Norbert
, p. 4667 - 4677 (2007/10/03)
The cryptophycins are a family of cyclic depsipeptides with four retrosynthetic units A to D which correspond to the respective amino acids and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres
Enantioselective Synthesis of (+)-Cryptophycin 52 (LY355703), a Potent Antimitotic Antitumor Agent
Ghosh, Arun K.,Swanson, Lisa
, p. 9823 - 9826 (2007/10/03)
A highly enantioselective and convergent synthesis of cryptophycin 52 (2), an exceedingly potent cytotoxic agent, is described. Cryptophycin 52, a synthetic variant of the cryptophycin family, is currently undergoing clinical trials. The synthesis is conv
