245125-88-6Relevant articles and documents
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.
Asymmetric syntheses of potent antitumor macrolides cryptophycin B and arenastatin A
Ghosh, Arun K.,Bischoff
, p. 2131 - 2141 (2007/10/03)
Efficient and highly stereoselective syntheses of cryptophycin B and arenastatin A, potent cytotoxic agents, are described. An ester-derived titanium enolate mediated syn-aldol reaction was employed to generate the stereocenters C-5 and C-6. The route is convergent and provides a convenient access to the synthesis of structural variants of cryptophycins as well as members of its family. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004).
Total Synthesis of Cryptophycins-1, -3, -4, -24 (Arenastatin A), and -29, Cytotoxic Depsipeptides from Cyanobacteria of the Nostocaceae
White, James D.,Hong, Jian,Robarge, Lonnie A.
, p. 6206 - 6216 (2007/10/03)
A convergent synthesis of cryptophycins has been developed in which (5S,6R)-5-hydroxy-6-methyl-8-phenylocta-2(E),7(E)-dienoic acid (A) is coupled with an amino acid segment (B). Two stereo-selective routes to A are described, the first employing allylatio
