146553-06-2Relevant articles and documents
Rational design of the first difluorostatone-based PfSUB1 inhibitors
Giovani, Simone,Penzo, Maria,Brogi, Simone,Brindisi, Margherita,Gemma, Sandra,Novellino, Ettore,Savini, Luisa,Blackman, Michael J.,Campiani, Giuseppe,Butini, Stefania
, p. 3582 - 3586 (2014)
The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors.
A Convenient Synthesis Of Chiral Peptide Nucleic Acid (PNA) Monomers
Kosynkina, Larisa,Wang, Wei,Liang, T. Chyau
, p. 5173 - 5176 (1994)
Chiral peptide nucleic acid monomers containing amino acid side chains can be easily prepared from the BOC-protected amino acids.
Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
De Rosa, Maria,Lu, Lu,Zamaratski, Edouard,Sza?aj, Natalia,Cao, Sha,Wadensten, Henrik,Lenhammar, Lena,Gising, Johan,Roos, Annette K.,Huseby, Douglas L.,Larsson, Rolf,Andrén, Per E.,Hughes, Diarmaid,Brandt, Peter,Mowbray, Sherry L.,Karlén, Anders
, p. 897 - 911 (2017)
Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.
Synthesis and characterization of some atypical sphingoid bases
Saied, Essa M.,Le, Thuy Linh-Stella,Hornemann,Arenz, Christoph
, p. 4047 - 4057 (2018)
Sphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids, but also affects the lipophilic anchors comprised of different fatty acids on the one hand and different sphingoid bases on the other hand. The structural variations within different sphingoid bases e.g. in pathogens can be used to identify novel biomarkers and drug targets and the specific change in the profile of common and uncommon sphingolipids are associated with pathological conditions like diabetes or cancer. Therefore, the emerging field of sphingolipidomics is dedicated to collect data on the sphingolipidome of a cell and hence to assign changes therein to certain states of a cell or to pathological conditions. This powerful tool however is still limited by the availability of structural information about the individual lipid species as well as by the availability of appropriate internal standards for quantification. Herein we describe the synthesis of a variety of 1-deoxy-sphingoid bases. 1-DeoxySphingolipids have recently acquired significant attention due to its pathological role in the rare inherited neuropathy, HSAN1 but also as predictive biomarkers in diabetes type II. Some of the compounds synthesized and characterized herein, have been used and will be used to elucidate the correct structure of these disease-related lipids and their metabolites.
DIHYDROQUINOXALINE AND DIHYDROPYRIDOPYRAZINE DERIVATIVES AS RSV INHIBITORS
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Paragraph 0328-0330, (2022/01/24)
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
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.
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.
