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).
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).
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.
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.
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.
