96293-17-3Relevant articles and documents
Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases
Li, Linfeng,Chenna, Bala C.,Yang, Kai S.,Cole, Taylor R.,Goodall, Zachary T.,Giardini, Miriam,Moghadamchargari, Zahra,Hernandez, Elizabeth A.,Gomez, Jana,Calvet, Claudia M.,Bernatchez, Jean A.,Mellott, Drake M.,Zhu, Jiyun,Rademacher, Andrew,Thomas, Diane,Blankenship, Lauren R.,Drelich, Aleksandra,Laganowsky, Arthur,Tseng, Chien-Te K.,Liu, Wenshe R.,Wand, A. Joshua,Cruz-Reyes, Jorge,Siqueira-Neto, Jair L.,Meek, Thomas D.
supporting information, p. 11267 - 11287 (2021/08/16)
Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease - Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki? = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.
A reappraisal of the Ni-[(Benzylprolyl)amino]benzophenone complex in the synthesis of α,α-disubstituted amino acid derivatives
Watson, Morag E.,Jamieson, Craig,Kennedy, Alan R.,Mason, Andrew M.
, (2019/08/08)
α,α-Disubstituted alkenyl amino acid derivatives (e.g. Fmoc-S5-OH) are valuable monomers in the construction of stapled peptide derivatives. Synthetic access to these is possible using the Ni-[(Benzylprolyl)amino]benzophenone (BPB) complex as a chiral auxiliary. We discuss a reappraisal of the use of this, and demonstrate that epimerisation of the proline α-centre occurs during formation of the complex, leading to erosion in the enantiomeric excess of the final product. Modified conditions have been developed, providing the target compounds in high enantiomeric excess.
2-[ 18 F]Fluorophenylalanine: Synthesis by Nucleophilic 18 F-Fluorination and Preliminary Biological Evaluation
Modemann, Daniel J.,Zlatopolskiy, Boris D.,Urusova, Elizaveta A.,Zischler, Johannes,Craig, Austin,Ermert, Johannes,Guliyev, Mehrab,Endepols, Heike,Neumaier, Bernd
, p. 664 - 676 (2019/01/23)
2-[ 18 F]Fluorophenylalanine (2-[ 18 F]FPhe), a promising PET tracer for imaging of cerebral infarction and tumors, was efficiently prepared from an easily accessible iodonium salt precursor using Cu-mediated radiofluorination under 'low base' or 'minimalist' conditions. Whereas significant racemization was initially observed if the 'minimalist' protocol was applied for radiolabeling, it was completely suppressed by the careful adjustment of 18 F - preprocessing. The initial biological study revealed a higher uptake of 2-[ 18 F]FPhe in different tumor cells in comparison to that of [ 18 F]FET. In contrast to 4-[ 18 F]FPhe, which suffered from rapid defluorination in vivo, 2-[ 18 F]FPhe demonstrated a sufficient in vivo stability. Conclusively, 2-[ 18 F]FPhe is a promising PET probe that is now readily available using Cu-mediated radiofluorination under 'minimalist' or 'low base' conditions. The simplicity of the translation of the proposed procedures to automated synthesis modules allows a broad biological evaluation of 2-[ 18 F]FPhe. Notably, a novel protocol for the preparation of N -Boc protected amino acids from the respective Ni-Schiff base complexes was developed that avoided application of strongly acidic conditions.
