33965-47-8Relevant articles and documents
The synthesis and characterization of tetramic acid derivatives as Mdm2-p53 inhibitors
Muszak, Damian,?abuzek, Beata,Brela, Mateusz Z.,Twarda-Clapa, Aleksandra,Czub, Miroslawa,Musielak, Bogdan,Surmiak, Ewa,Holak, Tad A.
, p. 161 - 174 (2019/04/26)
We present syntheses, prediction of tautomer forms and activities of the second generation of the Mdm2-p53 inhibitors that are based on the tetramic acid scaffold. The inhibitors do not contain 6-chloroindole. Binding of these compounds to Mdm2 was checked by two orthogonal methods: the fluorescence polarization and the 1H-15N HSQC NMR titration experiments. We discovered that the 3-phenylthio-substituted tetramic acid derivatives exist in solution solely in their enol forms which is in contrast to the similar 3-aliphatic substituted derivatives. The inhibitory (Ki) and dissociation (KD) constants are in low micromolar ranges with the best binding compound 9a having KD = 2.9 μM. Furthermore, our data show that the compounds indeed bind to the p53-binding pocket of Mdm2 and do not cause dimerization of Mdm2. The current work provides solid base for further rational design of the Mdm2/p53 inhibitors.
Pd-catalyzed dimethylation of tyrosine-derived picolinamide for synthesis of (S)-N-Boc-2,6-dimethyltyrosine and its analogues
Wang, Xuning,Niu, Songtao,Xu, Lanting,Zhang, Chao,Meng, Lingxing,Zhang, Xiaojing,Ma, Dawei
supporting information, p. 246 - 249 (2017/11/27)
A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible a-chiral centers.
Asymmetric chemoenzymatic synthesis of N-acetyl-α-amino esters based on lipase-catalyzed kinetic resolutions through interesterification reactions
Da Silva, Marcos Reinaldo,De Mattos, Marcos Carlos,De Oliveira, Maria Da Concei??o Ferreira,De Lemos, Telma Leda Gomes,Ricardo, Nágila Maria Pontes Silva,De Gonzalo, Gonzalo,Lavandera, Iván,Gotor-Fernández, Vicente,Gotor, Vicente
, p. 2264 - 2271 (2014/03/21)
Several phenylalanine analogs have been synthesized through a four-step route starting from easily available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the best one for the production of a series of quaternary amino acids in moderate to excellent yields (52-95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were obtained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as a versatile enzyme for the resolution of these amino esters, finding the best results through interesterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was found depending on the chemical structure of the compound, achieving for the non- or para-substituted in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the ortho-nitro amino ester did not react.
Enzymatic synthesis of chiral phenylalanine derivatives by a dynamic kinetic resolution of corresponding amide and nitrile substrates with a multi-enzyme system
Yasukawa, Kazuyuki,Asano, Yasuhisa
supporting information, p. 3327 - 3332 (2013/01/15)
Mutant α-amino-ε-caprolactam (ACL) racemase (L19V/L78T) from Achromobacter obae with improved substrate specificity toward phenylalaninamide was obtained by directed evolution. The mutant ACL racemase and thermostable mutant D-amino acid amidase (DaaA) from Ochrobactrum anthropi SV3 co-expressed in Escherichia coli (pACLmut/pDBFB40) were utilized for synthesis of (R)-phenylalanine and non-natural (R)-phenylalanine derivatives (4-OH, 4-F, 3-F, and 2-F-Phe) by dynamic kinetic resolution (DKR). Recombinant E. coli with DaaA and mutant ACL racemase genes catalyzed the synthesis of (R)-phenylalanine with 84% yield and 99% ee from (RS)-phenylalaninamide (400 mM) in 22 h. (R)-Tyrosine and 4-fluoro-(R)-phenylalanine were also efficiently synthesized from the corresponding amide compounds. We also co-expresed two genes encoding mutant ACL racemase and L-amino acid amidase from Brevundimonas diminuta in E. coli and performed the efficient production of various (S)-phenylalanine derivatives. Moreover, 2-aminophenylpropionitrile was converted to (R)-phenylalanine by DKR using a combination of the non-stereoselective nitrile hydratase from recombinamt E. coli and mutant ACL racemase and DaaA from E. coli encoding mutant ACL racemase and DaaA genes. Copyright
Synthesis and biological evaluation of new active For-Met-Leu-Phe-OMe analogues containing para-substituted Phe residues
Mollica, Adriano,Feliciani, Federica,Stefanucci, Azzurra,Costante, Roberto,Lucente, Gino,Pinnen, Francesco,Notaristefano, Daniela,Spisani, Susanna
experimental part, p. 418 - 426 (2012/08/28)
In the present study, we report synthesis and biological evaluation of the N-Boc-protected tripeptides 4a-l and N-For protected tripeptides 5a-l as new For-Met-Leu-Phe-OMe (fMLF-OMe) analogues. All the new ligands are characterized by the C-terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a-l and the antagonism of 4a-l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF-OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with -CH3 and -C(CH3)3, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i, containing -F and -I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed.
Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-substituted- pyrrolidine-2,4-dione derivatives
Han, Bao Feng,Shi, Qing Ming,Wang, Xian Feng,Liu, Jian Bo,Qiang, Sheng,Yang, Chun Long
, p. 1023 - 1026 (2012/10/08)
Ten novel 5-substituted derivatives of 3-(1-hydroxyethylidene)pyrrolidine- 2,4-dione were synthesized. The compounds were confirmed by IR, 1H NMR, MS and elemental analysis. The bioassay indicated that these compounds showed noticeable herbicid
Design, synthesis, and preliminary activity evaluation of novel peptidomimetics as aminopeptidase N/CD13 inhibitors
Li, Xun,Wang, Junli,Zhang, Lei,Xu, Wenfang
experimental part, p. 494 - 504 (2011/11/04)
The synthesis of a series of novel N-α-galloylated isoglutamic acid I-amide peptidomimetics is described. Their enzymatic inhibition against aminopeptidase N (APN/CD13) and matrix metalloproteinase-2 (MMP-2) was tested. The preliminary activity assay revealed that most of the compounds displayed selective inhibition against APN as compared with MMP-2, with IC50 values in a micromolar range. Within this series, compound 4 (IC 50a=10.2a±a.9μM) demonstrated comparable APN inhibition as compared with the positive control bestatin (IC 50a=a13.1aa0.7aμM), which might be a promising lead for further molecular optimizations. A new series of bi-peptide analogues containing amino acid or organic acid residues as elongated hydrophobic substituents inserting into S1 or S1 pocket was designed. Most of the target compounds showed potent and selective activities against APN/CD13 as compared with MMP-2. Compound 4 was comparable to bestatin and could be used as a potential lead for further development of APNIs.
INHIBITORS OF UDP-GALACTOPYRANOSE MUTASE THWART MYCOBACTERIAL GROWTH
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Page/Page column 49, (2009/12/05)
Compounds which inhibit microbial growth or attenuate the virulence of pathogen microorganisms. Compounds of the invention inhibit UDP-galactopyranose mutase (UGM) and have activity as inhibitors of microbial growth of microorganisms which contain this enzyme and particularly those microorganisms in which this enzyme is responsible for the incorporation of galactofuranose residues, particularly for uridine 5'-diphosphate (UDP) galactopyranose mutase. Compounds of the invention inhibit UDP- galactopyranose mutase (UGM) and have activity to attenuate virulence of pathogenic microorganisms, including mycobacteria.
Inhibitors of UDP-galactopyranose mutase thwart mycobacterial growth
Dykhuizen, Emily C.,May, John F.,Tongpenyai, Aimon,Kiessling, Laura L.
, p. 6706 - 6707 (2008/12/22)
Galactofuranose (Galf) residues are fundamental components of the cell wall of mycobacteria. A key enzyme, UDP-galactopyranose mutase (UGM), that participates in Galf incorporation mediates isomerization of UDP-Galf from UDP-galactopyranose (UDP-Galp). UGM is of special interest as a therapeutic target because the gene encoding it is essential for mycobacterial viability and there is no comparable enzyme in humans. We used structure-activity relationships and molecular design to devise UGM inhibitors. From a focused library of synthetic aminothiazoles, several compounds that block the UGM from Klebsiella pneumoniae or Mycobacterium tuberculosis were identified. These inhibitors block the growth of M. smegmatis. Copyright
Oleanolic acid and its derivatives: New inhibitor of protein tyrosine phosphatase 1B with cellular activities
Zhang, Yi-Nan,Zhang, Wei,Hong, Di,Shi, Lei,Shen, Qiang,Li, Jing-Ya,Li, Jia,Hu, Li-Hong
, p. 8697 - 8705 (2008/12/23)
Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, a series of competitive inhibitors were optimized from oleanolic acid, a natural triterpenoid identified against PTP1B by screening libraries of traditional Chinese medicinal herbs. Modifying at 3 and 28 positions, we obtained compound 13 with a Ki of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin.
