35909-92-3Relevant articles and documents
An efficient, stereocontrolled and versatile synthetic route to bicyclic partially saturated privileged scaffolds
Bond, Andrew D.,Hanby, Abigail R.,King, Thomas A.,Moss, Thomas A.,Sore, Hannah F.,Spring, David R.,Stewart, Hannah L.
supporting information, p. 6818 - 6821 (2020/07/04)
Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.
Design and synthesis of tripeptidyl furylketones as selective inhibitors against the β5 subunit of human 20S proteasome
Lü, Zirui,Li, Xiaona,Niu, Yan,Sun, Qi,Wang, Chao,Xi, Dandan,Xu, Fengrong,Xu, Ping,Zhou, Tongliang
, (2020/03/10)
A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against β1, β2 and β5 subunits revealed that they acted selectively on β5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 μM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 μg/L; AUC0?t, 680 μg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.
Method for selective removal of t-butyloxycarboryl from nitrogen
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Paragraph 0024-0025; 0026-0028; 0029-0031, (2018/03/26)
The invention discloses a method for selective removal of t-butyloxycarboryl from nitrogen. According to the synthesis method, directed at a reaction substrate having t-butyloxycarboryl and another acyl protecting group on a molecular nitrogen atom, in the presence of a selectfluor reagent, reaction is carried out in a solution for selective removal of t-butyloxycarboryl and retention of another acyl protecting group. The synthesis method provided by the invention is novel and efficient, is not reported in literature, and can be widely used in total synthesis and drug intermediate synthesis.
BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation
Li, Guisheng,Zatolochnaya, Olga V.,Wang, Xiao-Jun,Rodríguez, Sonia,Qu, Bo,Desrosiers, Jean-Nicolas,Mangunuru, Hari P. R.,Biswas, Soumik,Rivalti, Daniel,Karyakarte, Shuklendu D.,Sieber, Joshua D.,Grinberg, Nelu,Wu, Ling,Lee, Heewon,Haddad, Nizar,Fandrick, Daniel R.,Yee, Nathan K.,Song, Jinhua J.,Senanayake, Chris H.
supporting information, p. 1725 - 1729 (2018/04/14)
Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.
Metastin derivatives and use thereof
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Paragraph 0261, (2016/08/23)
The invention provides stable metastin derivatives having excellent biological activities (a cancer metastasis suppressing activity, a cancer growth suppressing activity, etc.). By modifying the constituent amino acids of metastin with specific modifying groups, metastin derivatives having more improved blood stability, etc. than native metastin and showing excellent cancer metastasis suppressing activity or cancer growth suppressing activity have been found. Furthermore, it has been found that these metastin derivatives exhibit effects of suppressing gonadotropic hormone secretion, suppressing sex hormone secretion, etc., which are wholly different from the effects heretofore known.
Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
Ettari, Roberta,Pinto, Andrea,Previti, Santo,Tamborini, Lucia,Angelo, Ilenia C.,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria,Grasso, Silvana,De Micheli, Carlo,Conti, Paola
, p. 7053 - 7060 (2015/11/11)
Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
Substrate derived peptidic α-ketoamides as inhibitors of the malarial protease PfSUB1
Kher, Samir S.,Penzo, Maria,Fulle, Simone,Finn, Paul W.,Blackman, Michael J.,Jirgensons, Aigars
supporting information, p. 4486 - 4489 (2015/02/19)
Peptidic α-ketoamides have been developed as inhibitors of the malarial protease PfSUB1. The design of inhibitors was based on the best known endogenous PfSUB1 substrate sequence, leading to compounds with low micromolar to submicromolar inhibitory activity. SAR studies were performed indicating the requirement of an aspartate mimicking the P1′ substituent and optimal P1-P4length of the non-prime part. The importance of each of the P1-P4amino acid side chains was investigated, revealing crucial interactions and size limitations.
Continuous flow synthesis of α-halo ketones: Essential building blocks of antiretroviral agents
Pinho, Vagner D.,Gutmann, Bernhard,Miranda, Leandro S. M.,De Souza, Rodrigo O. M. A.,Kappe, C. Oliver
, p. 1555 - 1562 (2014/03/21)
The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ～4.5 h (87% yield).
Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study
Thanigaimalai, Pillaiyar,Konno, Sho,Yamamoto, Takehito,Koiwai, Yuji,Taguchi, Akihiro,Takayama, Kentaro,Yakushiji, Fumika,Akaji, Kenichi,Kiso, Yoshiaki,Kawasaki, Yuko,Chen, Shen-En,Naser-Tavakolian, Aurash,Sch?n, Arne,Freire, Ernesto,Hayashi, Yoshio
, p. 436 - 447 (2013/10/01)
This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(-pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1′ position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease
Gros, Guillaume,Martinez, Lorena,Gimenez, Anna Servat,Adler, Paula,Maurin, Philippe,Wolkowicz, Roland,Falson, Pierre,Hasserodt, Jens
supporting information, p. 5407 - 5413 (2013/09/02)
Non-peptidomimetic drug-like protease inhibitors have potential for circumventing drug resistance. We developed a much-improved synthetic route to our previously reported inhibitor candidate displaying an unusual quaternized hemi-aminal. This functional group forms from a linear precursor upon passage into physiological media. Seven variants were prepared and tested in cellulo with our HIV-1 fusion-protein technology that result in an eGFP-based fluorescent readout. Three candidates showed inhibition potency above 20 μM and toxicity at higher concentrations, making them attractive targets for further refinement. Importantly, our class of original inhibitor candidates is not recognized by two major multidrug resistance pumps, quite in contrast to most clinically applied HIV-1 protease inhibitors.
