95687-41-5Relevant academic research and scientific papers
LINCOSAMIDE ANTIBIOTICS AND USES THEREOF
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Paragraph 00387, (2021/11/26)
Provided are compounds of Formula (I) for the treatment of infectious and inflammatory diseases. The compounds described herein are lincosamides modified at the amino acid (southern) region. The compounds may have further modification at the C-7 position of the aminooctose (northern) region, thus distinguishing them from lincomycin and clindamycin. Also provided are methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating infectious diseases using the disclosed compounds.
Practical Gram-Scale Synthesis of Iboxamycin, a Potent Antibiotic Candidate
Mason, Jeremy D.,Myers, Andrew G.,Pote, Aditya R.,Terwilliger, Daniel W.
, p. 11019 - 11025 (2021/08/03)
A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.
FUSED HETEROCYCLIC BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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, (2020/05/29)
The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
NOVEL BENZODIAZEPINE DERIVATIVES AND USES THEREOF
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, (2019/12/24)
The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.
Scale-up Synthesis of Tesirine
Tiberghien, Arnaud C.,Von Bulow, Christina,Barry, Conor,Ge, Huajun,Noti, Christian,Collet Leiris, Florence,McCormick, Marc,Howard, Philip W.,Parker, Jeremy S.
, p. 1241 - 1256 (2018/09/06)
This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody-drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody-drug conjugates in multiple clinical trials, four of them pivotal.
An Immucillin-Based Transition-State-Analogous Inhibitor of tRNA-Guanine Transglycosylase (TGT)
Hohn, Christoph,H?rtsch, Adrian,Ehrmann, Frederik Rainer,Pfaffeneder, Toni,Trapp, Nils,Dumele, Oliver,Klebe, Gerhard,Diederich, Fran?ois
supporting information, p. 6750 - 6754 (2016/05/11)
Shigellosis is one of the most severe diarrheal diseases worldwide without any efficient treatment so far. The enzyme tRNA-guanine transglycosylase (TGT) has been identified as a promising target for small-molecule drug design. Herein, we report a transition-state analogue, a small, immucillin-derived inhibitor, as a new lead structure with a novel mode of action. The complex inhibitor synthesis was accomplished in 18 steps with an overall yield of 3 %. A co-crystal structure of the inhibitor bound to Z. mobilis TGT confirmed the predicted conformation of the immucillin derivative in the enzyme active site.
New optically active 4-alkoxyprolinol ethers derived from trans-4-Hydroxy-L-proline
Friedemann, Nora M.,Eustergerling, Astrid,Nubbemeyer, Udo
experimental part, p. 837 - 843 (2012/03/11)
(2S,4R)-trans-4-Hydroxy-L-proline has been used as thechiral-pool source in the efficient syntheses of optically active protected 4-hydroxyprolinols. After N-acyl protection andester formation, the first ether moiety was introduced maintaining the chiral
AURORA KINASE COMPOUNDS AND METHODS OF THEIR USE
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Page/Page column 217-218, (2011/08/04)
Provided herein are pyrrolotriazine compounds for treatment of Aurora kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
Structure-guided minimalist redesign of the L-fuculose-1-phosphate aldolase active site: Expedient synthesis of novel polyhydroxylated pyrrolizidines and their inhibitory properties against glycosidases and intestinal disaccharidases
Garrabou, Xavier,Gomez, Livia,Joglar, Jesus,Gil, Sergi,Parella, Teodor,Bujons, Jordi,Clapes, Pere
experimental part, p. 10691 - 10706 (2010/11/19)
A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz = benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N-Cbz-amino aldehydes including N-Cbz-prolinal derivatives. FucA F131A showed an aldol activity of 62μmol-1mg-1 with (R)-N-Cbz-prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)-amino aldehydes gave exclusively the anti configured aldol adducts whereas their 5 counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)and with (S)-N-Cbz-prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N-Cbz-prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π-cation interaction with the residue K205' and to efficient contact between the substrate and the mechanistically important Y113' and Y209' residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) and 1,4-dideoxy-1,4-iminoD-arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.
Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues
Vaněk, Václav,Budě?ínsky, Milo?,Rinnová, Markéta,Rosenberg, Ivan
experimental part, p. 862 - 876 (2009/05/09)
trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.
