80963-12-8Relevant academic research and scientific papers
Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome
Zhang, Hao,Hsu, Hao-Chi,Kahne, Shoshanna C.,Hara, Ryoma,Zhan, Wenhu,Jiang, Xiuju,Burns-Huang, Kristin,Ouellette, Tierra,Imaeda, Toshihiro,Okamoto, Rei,Kawasaki, Masanori,Michino, Mayako,Wong, Tzu-Tshin,Toita, Akinori,Yukawa, Takafumi,Moraca, Francesca,Vendome, Jeremie,Saha, Priya,Sato, Kenjiro,Aso, Kazuyoshi,Ginn, John,Meinke, Peter T.,Foley, Michael,Nathan, Carl F.,Darwin, K. Heran,Li, Huilin,Lin, Gang
supporting information, p. 6262 - 6272 (2021/05/29)
Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
Esterase-sensitive prodrugs of a potent bisubstrate inhibitor of nicotinamide n-methyltransferase (Nnmt) display cellular activity
van Haren, Matthijs J.,Gao, Yongzhi,Buijs, Ned,Campagna, Roberto,Sartini, Davide,Emanuelli, Monica,Mateuszuk, Lukasz,Kij, Agnieszka,Chlopicki, Stefan,de Castilla, Pol Escudé Martinez,Schiffelers, Raymond,Martin, Nathaniel I.
, (2021/09/16)
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
MACROCYCLIC COMPOUNDS AS PROTEASOME INHIBITORS
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Paragraph 0557, (2019/05/02)
The compounds of the present invention are represented by the following compounds having Formula I and Formula (I'): where the substituents R1, R2, R2', R3, R4, R5, R', R", X, Y, and Z are as defined herein and where the substituents R1, R2, R3, R4, R5, R', R", X, Y, and Z are as defined herein. These compounds are used in the treatment of bacterial infections, parasite infections, fungal infections, cancer, immunologic disorders, autoimmune disorders, neurodegenerative diseases and disorders, inflammatory disorders, or muscular dystrophy or for providing immunosuppression for transplanted organs or tissues.
The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain
Brown, Alan D.,Bagal, Sharan K.,Blackwell, Paul,Blakemore, David C.,Brown, Bruce,Bungay, Peter J.,Corless, Martin,Crawforth, James,Fengas, David,Fenwick, David R.,Gray, Victoria,Kemp, Mark,Klute, Wolfgang,Malet Sanz, Laia,Miller, Duncan,Murata, Yoshihisa,Payne, C. Elizabeth,Skerratt, Sarah,Stevens, Edward B.,Warmus, Joseph S.
supporting information, p. 230 - 239 (2018/12/11)
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Batch and Continuous-Flow One-Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents
Audubert, Clément,Gamboa Marin, Oscar Javier,Lebel, Hélène
supporting information, p. 6294 - 6297 (2017/05/19)
A novel synthesis of trimethylsilyldiazomethane (TMSCHN2) by diazotization of trimethylsilylmethylamine (TMSCH2NH2) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN2. Other silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents. The applicability of the process is highlighted by disclosure of batch and continuous flow one-pot esterification and 1,3-dipolar cycloaddition processes. Furthermore, the high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flow is disclosed. Finally, work-up and purification procedures are reported for the preparation of a 2-MeTHF solution of TMSCHN2, which can be used in rhodium-catalyzed methylenation and homologation reactions.
Total Synthesis of the Diglycosidic Tetramic Acid Ancorinoside A
Petermichl, Markus,Schobert, Rainer
supporting information, p. 14743 - 14746 (2017/10/27)
Ancorinoside A, a metabolite of a sponge Ancorina sp., was prepared in 18 steps as the first derivative of this class of glycosylated 3-acyltetramic acids. It features a β-d-glucopyranosyl-(1→4)-β-d-galacturonic acid linked to a d-aspartic acid derived te
N-Pyrrolidine-based α/β-peptides incorporating ABOC, a constrained bicyclic β-amino acid, for asymmetric aldol reaction catalysis
Milbeo, Pierre,Maurent, Kelly,Moulat, Laure,Lebrun, Aurélien,Didierjean, Claude,Aubert, Emmanuel,Martinez, Jean,Calmès, Monique
, p. 1706 - 1715 (2016/03/08)
A series of N-pyrrolidine-based α,β-peptide catalysts incorporating a constrained 2-aminobicyclo[2.2.2]octane carboxylic acid (ABOC) residue were synthesized and evaluated in the asymmetric aldol reaction from acetone and some p-substituted benzaldehydes. Their catalytic properties were shown to be highly dependent on the amino acid sequences and on the absolute configuration of the ABOC residue that played a determinant role. Among the peptides tested, the heterochiral tripeptide H-Pro-(R)-ABOC-Asp-OCH3 13, that adopts a turn conformation in the solid state, proved to be the most efficient catalyst affording β-hydroxy ketones in high yields and good enantioselectivities (up to 87%).
Thermodynamic and Structural Investigation of Synthetic Actinide-Peptide Scaffolds
Safi, Samir,Jeanson, Aurélie,Roques, Jérome,Solari, Pier Lorenzo,Charnay-Pouget, Florence,Den Auwer, Christophe,Creff, Ga?lle,Aitken, David J.,Simoni, Eric
supporting information, p. 877 - 886 (2016/02/03)
The complexation of uranium and europium, in oxidation states +VI and +III, respectively, was investigated with pertinent bio-inorganic systems. Three aspartate-rich pentapeptides with different structural properties were selected for study to rationalize the structure-affinity relationships. Thermodynamic results, crosschecked by both isothermal titration calorimetry and time-resolved laser fluorescence spectroscopy, showed different affinity depending on the peptide for both Eu(III) and U(VI). The thermodynamic aspects were correlated to structural predictions, which were acquired by density functional theory quantum chemical calculations and from IR and extended X-ray absorption fine structure experiments. The combination of these microscopic properties revealed that carbonyl-metal interactions affected the entropy in the case of europium, while the larger uranyl cation was mostly affected by preorganization and steric effects, so that the affinity was enhanced through enthalpy. The approach described here revealed various microscopic aspects governing peptide actinide affinity. Highlighting these mechanisms should certainly contribute to the rational synthesis of higher affinity biomimetic aspartic ligands.
Visible-Light Photoredox Synthesis of Chiral α-Selenoamino Acids
Jiang, Min,Yang, Haijun,Fu, Hua
supporting information, p. 1968 - 1971 (2016/06/01)
N-Acetoxyphthalimide derivatives of two genetically coded proteinogenic amino acids, l-aspartic acid and glutamic acid, were used as visible light photoredox chiral sources and radical precursors, diorganyl diselenides were used as the radical acceptors,
Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication
Maiti, Munmun,Maiti, Mohitosh,Rozenski, Jef,De Jonghe, Steven,Herdewijn, Piet
, p. 5158 - 5174 (2015/05/13)
In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2′-C-methyl containing nucleosides, 2′-C-Me-cytidine, 2′-C-Me-uridine and 2′-C-Me-2′-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5′-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ～550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.
