4931-66-2Relevant articles and documents
Synthesis of chiral 5-substituted 2-pyrrolidinones: An unusual one-step transformation
Wei, Zhong-Yong,Knaus, Edward E.
, p. 4439 - 4442 (1993)
An efficient methodology for the enantioselective synthesis of γ-lactams, using a one-pot reaction of chiral N-alkoxycarbonyl γ-amino α,β-unsaturated carboxylates with magnesium in methanol, afforded the target chiral compounds in high chemical yield (87-95%) and optical purity (96-99% ee).
Biotransformation of Licochalcone A by transgenic crown galls of Panax quinquefolium
Li, Jiayuan,Li, Ning,Huang, Bing,Zhao, Weihong,Wang, Wenli,Si, Yingying,Yan, Chunyan
, p. 72 - 76 (2014)
Licochalcone A, as main constituent of Chinese Gancao (Glycyrrhiza inflate Bat), is responsible for thechemopreventive effect of the herbal. In order to get the bioactive modified molecules of Licochalcone A,it was biotransformed using transgenic crown galls of Panax quinquefolium to afford 9 products includinga new alkaloid together with 8 known compounds. Their structures were elucidated by physicochemicaland spectral methods as: methyl(12S)-1-[(5-formylfuran-2-yl)methyl]-5-oxopyrrolidine-2-carboxylate(1), methyl(12S)-1-[2-(furan-2-yl)-2-oxoethyl]-5-oxopyrrolidine-2-carboxylate (2), 5-hydroxymethyl-2-furfural (3), (S)-methylpyroglutamate (4), 4-hydroxy-2-methoxy-5-(2-methylbut-3-en-2-yl) benz-aldehyde (5), 4-hydroxybenzoicacid (6), dibutyl phthalate (7), 3β,6α,12β,25-tetrahydroxy-(20S,24R)-epoxy-dammarane (8), β-sitosterol (9).Among them, compounds 5 and 6 were transformed from Licochalcone A, while 14 and 8 were derivedfrom the culture medium stimulated by the substrate. Furthermore, their cancer chemopreventive effectwere tested by the assay of NQO1 (NAD(P)H: quinine oxidoreductase 1) inducing activities in Hepa 1c1ccells.
A catalytic one-step process for the chemo- and regioselective acylation of monosaccharides
Kawabata, Takeo,Muramatsu, Wataru,Nishio, Tadashi,Shibata, Takeshi,Schedel, Hartmut
, p. 12890 - 12895 (2007)
An organocatalytic method for the chemo- and regioselective acylation of monosaccharides has been developed. Treatment of octyl β-D-glucopyranoside with isobutyric anhydride in the presence of 10 mol % of a C2- symmetric chiral 4-pyrrolidinopyridine catalyst (1) at -50°C gave the 4-O-isobutyryl derivative as the sole product in 98% yield. Thus, chemoselective acylation, favoring a secondary hydroxyl group in the presence of a free primary hydroxyl group, and regioselective acylation, favoring one of three secondary hydroxyl groups, took place with perfect selectivity. A competitive acylation between octyl β-D-glucopyranoside and a primary alcohol (2-phenylethanol) with 1.1 equiv of isobutyric anhydride in the presence of 1 gave the 4-O-isobutyrate of octyl β-D-glucopyranoside with 99% regioselectivity in 98% yield, which indicates that acylation of the secondary hydroxyl group at C(4) of the carbohydrate proceeds in an accelerative manner. A possible mechanism, involving multiple hydrogen-bonding between 1 and the monosaccharide, is proposed for the chemo- and regioselective acylation.
Studies on pyrrolidinones: Some attempts to improve the synthesis of methyl N-(3,4,4′,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81) by using N-acyl iminium salts methodologies
Bourry, Anne,Pitard, Franck,Rigo, Benoit,Sanz, Gerard,Camus, Fabrice,Norberg, Bernadette,Durant, Francois,Couturier, Daniel
, p. 109 - 118 (2002)
Some ways to use the N-acyl iminium salt methodologies to synthesize a new inhibitor of tubulin polymerization, methyl N-(3,4,4′,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81) were studied. The most interesting reactions utilize a new pyroglutamic lactone (3-(3,4,5-trimethoxyphenyl)dihydropyrrolo[1,2-c]oxazole-1,5-dione).
Revised Structure of Anthelvencin A and Characterization of the Anthelvencin Biosynthetic Gene Cluster
Aubry, Céline,Clerici, Paolo,Gerbaud, Claude,Lautru, Sylvie,Micouin, Laurent,Pernodet, Jean-Luc
, p. 945 - 951 (2020)
Anthelvencins A and B are pyrrolamide metabolites produced by Streptomyces venezuelae ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate antibacterial activities. In this study, we revise the structure of anthelvencin A and identify a third anthelvencin metabolite, bearing two N-methylated pyrrole groups, which we named anthelvencin C. We sequenced the genome of S. venezuelae ATCC 14583 and identified a gene cluster predicted to direct the biosynthesis of anthelvencins. Functional analysis of this gene cluster confirmed its involvement in anthelvencin biosynthesis and allowed us to propose a biosynthetic pathway for anthelvencins. In addition to a nonribosomal peptide synthetase (NRPS), the assembly of anthelvencins involves an enzyme from the ATP-grasp ligase family, Ant23. We propose that Ant23 uses a PCP-loaded 4-aminopyrrole-2-carboxylate as substrate. As observed for the biosynthesis of the other pyrrolamides congocidine (produced by Streptomyces ambofaciens ATCC 25877) and distamycin (produced by Streptomyces netropsis DSM 40846), the NRPS assembling anthelvencins is composed of stand-alone domains only. Such NRPSs, sometimes called type II NRPSs, are less studied than the classical multimodular NRPSs. Yet, they constitute an interesting model to study protein-protein interactions in NRPSs and are good candidates for combinatorial biosynthesis approaches.
Design, synthesis and evaluation of hydrazine and acyl hydrazone derivatives of 5-pyrrolidin-2-one as antifungal agents
Billamboz, Muriel,Dascalu, Anca-Elena,Fayeulle, Antoine,Furman, Christophe,Ghinet, Alina,Lipka, Emmanuelle,Rigo, Beno?t
, (2020)
Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent – hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the –NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate “fungicide-like” properties and were devoted of cytotoxicity.
Enantioselective N-heterocyclic carbene-catalysed intermolecular crossed benzoin condensations: Improved catalyst design and the role of in situ racemisation
Delany, Eoghan G.,Connon, Stephen J.
supporting information, p. 248 - 258 (2021/01/14)
The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl substituent. It was found that increasing both the steric requirement and the electron-withdrawing characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry, however both quenching the reaction at different times and deuterium incorporation experiments involving the product revealed that this is complicated by product racemisation in situ (except in the case of benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-good yields with moderate to excellent enantioselectivity.
Identification of a Pyrrole Intermediate Which Undergoes C-Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis
Kim, Minje,Liu, Hung-wen,Ren, Daan,Wang, Shao-An
supporting information, p. 17148 - 17154 (2021/06/28)
Showdomycin is a C-nucleoside bearing an electrophilic maleimide base. Herein, the biosynthetic pathway of showdomycin is presented. The initial stages of the pathway involve non-ribosomal peptide synthetase (NRPS) mediated assembly of a 2-amino-1H-pyrrole-5-carboxylic acid intermediate. This intermediate is prone to air oxidation whereupon it undergoes oxidative decarboxylation to yield an imine of maleimide, which in turn yields the maleimide upon acidification. It is also shown that this pyrrole intermediate serves as the substrate for the C-glycosidase SdmA in the pathway. After coupling with ribose 5-phosphate, the resulting C-nucleoside undergoes a similar sequence of oxidation, decarboxylation and deamination to afford showdomcyin after exposure to air. These results suggest that showdomycin could be an artifact due to aerobic isolation; however, the autoxidation may also serve to convert an otherwise inert product of the biosynthetic pathway to an electrophilic C-nucleotide thereby endowing showdomycin with its observed bioactivities.
Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
supporting information, p. 382 - 387 (2021/01/13)
The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
Alnemy, Sydney,Bradley, Michael J.,Chuaqui, Claudio,Ciblat, Stephane,Hamman, Kristin B.,Hu, Shanhu,Kabro, Anzhelika,Ke, Nan,Malojcic, Goran,Marineau, Jason J.,Mihalich, Janessa,Roy, Stephanie,Savinainen, Anneli,Schmidt, Darby,Waters, Nigel J.,Whitmore, Kenneth Matthew,Wilsily, Ashraf,Winter, Dana K.,Zahler, Robert
, (2021/11/18)
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
