40052-13-9Relevant articles and documents
Design, Synthesis, and Conformational Analysis of Proposed β-Turn Mimics from Isoxazoline-Cyclopentane Aminols
Memeo, Misal Giuseppe,Mella, Mariella,Montagna, Valentina,Quadrelli, Paolo
, p. 16374 - 16378 (2015)
Constrained aminols from oxazanorbornene derivatives have the geometrical features to be used as β-turn inducers. Four different stereoisomers were prepared and spectroscopically characterized (MD calculations, NMR-titration and VT-NMR experiments). Temperature coefficients in DMSO are indicative for the existence of an intramolecular hydrogen bond. Chirooptical properties revealed a β-turn arrangement of all the synthesized compounds, where, depending on the absolute configuration of the cyclopentane spacer, they can be labeled as left- or right-handed turns.
Biomimetic regioselective and high-yielding Cu(i)-catalyzed dimerization of sinapate esters in green solvent Cyrene: Towards sustainable antioxidant and anti-UV ingredients
Mention, Matthieu M.,Flourat, Amandine L.,Peyrot, Cédric,Allais, Florent
supporting information, p. 2077 - 2085 (2020/04/08)
Naturally occurring sinapic acid and its esters are anti-UV and antiradical chemicals. This work aimed at designing an industrially relevant sustainable synthetic pathway allowing their selective β-β′ dimerization to enhance their properties with a view to use them in commercial applications such as functional additives for cosmetics, plastics and food/feed. A copper(i)-catalyzed procedure involving pyridine and O2 from air was developed and greened up using the REACH-compliant bio-based solvent Cyrene. Upon optimizing further through design of experiments, this sustainable synthetic process was successfully implemented to various sinapate esters and was validated on the multigram scale. Antiradical activities of the resulting β-β′ disinapate esters were benchmarked against commercial antioxidants, whereas their UV absorbance was compared to that of sinapoyl malate, a natural anti-UV compound found in plants and that of Octinoxate, a widely used commercial sunscreen ingredient. Results showed that these dimers were better radical scavengers, and not only exhibited a better UV absorbance but also covered both UV-A and UV-B regions.
Synthesis and evaluation of new 4-peptidamido-2-fluorobenzyl phosphoramide mustard conjugates as prodrugs activated by prostate-specific antigen
Aloysius, Herve,Hu, Longqin
, (2020/06/17)
In our continued efforts to develop targeted prodrugs activated by prostate-specific antigen (PSA), we designed and synthesized novel phosphoramide mustard peptide conjugates using previously optimized PSA substrates. Initial Nu/Nu mouse PK studies indicated that prodrug I (glutaryl-Hyp-Ala-Ser-Chg-Gln-NH-2-F-Bn-phosphoramide mustard) exhibits high clearance with significant extrahepatic metabolism in vivo. Substrate optimization studies were thus carried out to further improve PSA specificity and enable the design of prodrugs with reduced in vivo clearance and enhanced tumor selectivity. To assess the utility of the newly optimized sequences as promoieties, they were coupled to phosphoramide mustard using a 4-amino-2-fluorobenzyl alcohol linker akin to prodrug I. In the presence of human PSA, prodrug I was rapidly cleaved with a half-life (t1/2) of 35 min. Prodrugs II (glutaryl-Ser-Ala-Ser-Chg-Gln-NH-2-F-Bn-phosphoramide mustard) and III (GABA ← mGly-Ala-Ser-Chg-Gln-NH-2-F-Bn-phosphoramide mustard) were hydrolyzed at slower rates with t1/2 values of 80 and 107 min, respectively. These results we observed here are different from our previously reported data but may be explained by the fact that PSA-activated release of phosphoramide mustard and reactive quinonimine methides resulted in mechanism-based inhibition of PSA, thereby preventing further hydrolysis of prodrugs I–III. Prodrug I was cytotoxic to PSA-producing LNCaP cells with an IC50 value of 7.3 μM and demonstrated 14-fold selectivity over the non-PSA-producing DU145. Despite its poor in vitro antiproliferative activity (IC50 = 30 μM), prodrug III was found to be more stable against non-PSA-mediated hydrolysis compared with prodrug I as revealed by metabolite profiling studies, which was in agreement with its improved stability in human hepatocyte cultures. These results suggested that a combination of the peptide sequence GABA ← mGly-Ala-Ser-Chg-Gln with optimal linkers and/or other cytotoxic agents can help achieve an adequate balance between PSA cleavage rate and enhanced resistance to non-PSA-mediated hydrolysis. [Figure not available: see fulltext.]
