87694-49-3Relevant academic research and scientific papers
Synthesis and evaluation of novel iminosugars prepared from natural amino acids
Puet, Alejandro,Domínguez, Gema,Ca?ada, Francisco Javier,Pérez-Castells, Javier
, (2021/06/28)
Cyclopropanated iminosugars have a locked conformation that may enhance the inhibitory activity and selectivity against different glycosidases. We show the synthesis of new cyclopropane-containing piperidines bearing five stereogenic centers from natural amino acids L-serine and L-alanine. Those prepared from the latter amino acid may mimic L-fucose, a natural-occurring monosaccharide involved in many molecular recognition events. Final compounds prepared from L-serine bear S configurations on the C5 position. The synthesis involved a stereoselective cyclopropanation reaction of an α,β-unsaturated piperidone, which was prepared through a ring-closing metathesis. The final compounds were tested as possible inhibitors of different glycosidases. The results, although, in general, with low inhibition activity, showed selectivity, depending on the compound and enzyme, and in some cases, an unexpected activity enhancement was observed.
Synthesis of chiral branched allylamines through dual photoredox/nickel catalysis
Garbacz, Mateusz,Stecko, Sebastian
supporting information, p. 8578 - 8585 (2021/10/20)
Allylamines are versatile building blocks in the synthesis of various naturally occurring products and pharmaceuticals. In contrast to terminal allylamines, the methods of synthesis of their branched congeners with internal, stereodefined double bonds are less explored. This work describes a new approach for the preparation of allylaminesviacross-coupling of alkyl bromides with simple 3-bromoallylamines by merging the photoredox approach and Ni catalysis. The reaction proceeds under mild conditions, under blue light irradiation, and in the presence of an organic dye, 4CzIPN, as a photocatalyst. The scope of suitable reaction partners is broad, including alkyl bromides bearing reactive functionalities (e.g., esters, nitriles, aldehydes, ketones, epoxides) andN-protected allylamines, as well asN-allylated secondary and tertiary amines and heterocycles. The employment of non-racemic starting materials allows for rapid and easy construction of complex multifunctional allylamine derivatives without the loss of enantiomeric purity.
Synthesis and Characterization of Optically Pure Gamma-PNA Backbones by SIBX-Mediated Reductive Amination
Periyalagan, Alagarsamy,Kim, Yong-Tae,Hong, In Seok
, p. 1304 - 1309 (2021/08/09)
Chiral peptide nucleic acid (PNA) is a derivative of regular PNA by introducing a chiral center to its backbone, and is known to bind more strongly to DNA or RNA than regular PNA. In particular, in the case of a γ-backbone, the L isomer stabilizes the PNA/DNA duplex, and the D-isomer has the opposite effect. Therefore, the synthesis of an optically pure γ-backbone is very important. Here, we report a novel synthetic strategy for the suppression of epimerization during the synthesis of the γ-PNA backbone. A stabilized form of 2-iodoxybenzoic acid (SIBX) was used as an oxidative reagent in the key intermediate of the N-Boc-amino acetaldehyde synthesis. This paper reports (1) the synthesis and comparison of three different γ-PNA backbones (lysine, alanine, and glutamate) by three different synthetic routes (SIBX, lithium aluminum hydride, and Red-Al) and (2) the determination of chiral purity from their derivative compounds. The enantiomeric excess purity of SIBX-mediated γ-PNA backbones was determined to be more than 99.4%, as ascertained by the high-performance liquid chromatography (HPLC) chromatogram on a standard RP-C18 column. It is comparatively higher than that of the other methods examined in this work.
Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L
Aggarwal, Anupriya,Ashhurst, Anneliese S.,Bedding, Max J.,Beretta, Laura,Drelich, Aleksandra,Gerwick, William H.,Hook, Vivian,Larance, Mark,Li, Linfeng,McKerrow, James H.,Meek, Thomas D.,O'Donoghue, Anthony J.,Payne, Richard J.,Pwee, Dustin,Skinner, Danielle,Stoye, Alexander,Tang, Arthur H.,Tseng, Chien-Te,Turville, Stuart,Yoon, Michael C.,Fajtová, Pavla
supporting information, (2021/11/18)
Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.
Probing α-Amino Aldehydes as Weakly Acidic Pronucleophiles: Direct Access to Quaternary α-Amino Aldehydes by an Enantioselective Michael Addition Catalyzed by Br?nsted Bases
García-Urricelqui, Ane,de Cózar, Abel,Mielgo, Antonia,Palomo, Claudio
supporting information, p. 2483 - 2492 (2020/12/25)
The high tendency of α-amino aldehydes to undergo 1,2-additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α-amino aldehydes. Herein, it is demonstrated that the chemistry of α-amino aldehydes may be expanded beyond these limits by documenting the first direct α-alkylation of α-branched α-amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo- and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α-amino aldehyde is key for reaction stereocontrol.
Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-Catalyzed C?H Glycosylation of Alkenes
Chen, Gong,He, Gang,Qiao, Tianjiao,Sun, Qikai,Wang, Quanquan,Zhang, Huixing
supporting information, p. 19620 - 19625 (2021/08/09)
C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C?H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C?H bond of allylamines and the δ C?H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.
Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I
Amatuni, Alexander,Shuster, Anton,Adibekian, Alexander,Renata, Hans
, p. 1318 - 18,1326 (2020/09/02)
Amatuni et al. established a concise chemoenzymatic synthesis of cepafungin I. The route enabled access to a chemoproteomic probe, revealing high selectivity for proteasome subunits β5/2. Potent inhibition was associated with the macrocyclic hydroxyl group and lipid tail. Cepafungin I exhibited similar mode of action with the clinical drug bortezomib. The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I toward the β2 and β5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I.
Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine
Bihel, Frédéric,Bricard, Jacques,Garnier, Delphine,Gizzi, Patrick,Leloire, Maeva,Mohr, Julie,Schmitt, Martine,Schneider, Séverine,Tang, Shuang-Qi
, p. 15347 - 15359 (2020/11/30)
Herein, we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a N-O bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of the configuration depending on the steric hindrance in the vicinity of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one.
Structurally Diverse Acyl Bicyclobutanes: Valuable Strained Electrophiles
Attard, Riley H.,Gardiner, Michael G.,Malins, Lara R.,Schwartz, Brett D.,Zhang, Meng Yao
supporting information, p. 2808 - 2812 (2020/03/04)
Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.
Topical ‘dual-soft’ glucocorticoid receptor agonist for dermatology
Carnerup, Martin A.,Dack, Kevin N.,Eirefelt, Stefan,Henriksson, Krister,Johnson, Patrick S.,Ollerstam, Anna K.,Stahlhut, Martin
supporting information, (2020/07/21)
Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids. Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver (“dual-soft”) it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids. Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.
