75172-31-5Relevant articles and documents
Electrostatics Favor PNA : DNA Stability over Stereochemistry in Pyrrolidine-Based Cationic Dual-Backbone PNA Analogues
Sharma, Ashwani,More, Shahaji H.,Ganesh, Krishna N.
, p. 1146 - 1155 (2021/02/09)
Modifications to the peptide nucleic acid (PNA) backbone has been well known to alter the thermodynamical parameters of PNA : DNA complexes to broaden their utility for different applications. Electrostatic interactions between a modified PNA having a positively charged backbone and the negatively charged DNA has been shown to enhance thermal stabilities of PNA : DNA complexes at various instances. On the other hand, chiral introduction in PNA backbone leads to stereochemical preference that affects binding properties. However, the interplay between electrostatics and stereochemistry has not been systematically studied so far. Herein, we report the synthesis and biophysical characterization of cationic PNA named dapPNA, first of its kind, having a dual PNA backbone constituting of a pyrrolidine ring having a β-substitution. One of the aims of this study was to investigate the role of electrostatics over stereochemical preferences. The results show that electrostatic attraction between cationic dapPNA and negatively charged DNA overcomes the unfavorable stereochemical effects and enhances stability of PNA : DNA complexes. Moreover, two different PNA backbones derived from a single PNA monomer expands the repertoire of pyrrolidine based PNA analogues.
(3S,4S)-N-substituted-3,4-dihydroxypyrrolidines as ligands for the enantioselective Henry reaction
Rénio, Márcia R.R.,Sousa, Francisco J.P.M.,Tavares, Nélia C.T.,Valente, Artur J.M.,da Silva Serra, M. Elisa,Murtinho, Dina
, (2021/02/03)
The enantioselective Henry reaction is a very important and useful carbon–carbon bond forming reaction. The execution of this reaction requires the use of efficient chiral catalysts. In this work, in situ formed complexes of N-substituted dihydroxypyrrolidines, chiral ligands derived from L-tartaric acid and amines, were evaluated as catalysts in the enantioselective Henry reaction. The results showed that the nature of the N-substituent on the ligand significantly influences the outcome of the reaction. Best results were obtained using a Cu (II) complex of (3S,4S)-N-benzyl-3,4-dihydroxypyrrolidine, in the presence of DIPEA, for the reaction of aromatic aldehydes with nitromethane, at room temperature, originating products with er up to 92:8 (R:S) and conversions up to 96%. The interaction between the pyrrolidine ligand and the copper ion, in isopropanol, was followed by UV-vis spectrophotometry, showing a 1:1 stoichiometry and a binding constant of 4.4. The results obtained will contribute to the design and development of more efficient chiral catalysts for this type of reaction.
Preorganized helical chirality controlled homochiral self-assembly and circularly polarized luminescence of a quadruple-stranded Eu2 L 4 helicate
Cheng, Zhenyu,Gao, Ting,Han, Guoying,Li, Hongfeng,Yan, Pengfei,Yao, Yuan,Zhou, Yanyan
, p. 3312 - 3320 (2020/03/23)
β-Diketones are one of the most widely used ligands for sensitizing the luminescence of lanthanide complexes due to their excellent sensitization abilities. However, the difficulties in introducing chiral groups to take part in the electronic transitions of conjugated systems limit their application in lanthanide circularly polarized luminescence (CPL) materials. In view of the inherent chirality of the helical structure, herein, a pair of homochiral quadruple-stranded helicates, Eu2L4, is assembled based on chiral bis-β-diketonate ligands, wherein the two point chirality centers in the spacer preorganize the helical conformation of the ligand (3S,4S)/(3R,4R)-3,4-bis(4,4′-bis(4,4,4-trifluoro-1,3-dioxobutyl)phenoxyl)-1-benzylpyrrolidine, LSS/LRR. X-ray crystallographic analyses reveal that the R,R configurations of the chiral carbons in the spacer induce the M helical sense of the ligand, while the S,S configurations induce the P helical sense. Through the comprehensive spectral characterization in combination with semiempirical geometry optimization using the Sparkle/RM1 model, it is confirmed that the preorganized ligands successfully control the homochirality of the helicates. Moreover, the mirror-image CD and CPL spectra and NMR measurements confirm the formation of enantiomeric pairs and their diastereopurities in solution. Detailed photophysical and chiroptical characterization studies reveal that the helicates not only exhibit intense circularly polarized luminescence (CPL) with |glum| values reaching 0.10, but also show a high luminescence quantum yield of 34%. This study effectively combines the helical chirality of the helicates with the excellent sensitization ability of the β-diketones, providing an effective strategy for the syntheses of chiral lanthanide CPL materials.
Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors
Xie, Fangzhou,Yang, Fengzhi,Liang, Yaoyao,Li, Liang,Xia, Yu,Jiang, Faqin,Liu, Wenlu,Qi, Yunyue,Chowdhury, Sharmin Reza,Xie, Dongsheng,Fu, Lei
, p. 408 - 422 (2019/01/08)
Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC50 = 120, 1940 and 2670 nM against PTP1B, TCPTP and SHP2 respectively, and Papp = 1.74 × 10?6 cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.
Enantiospecific Synthesis of (3 R,4 R)-1-Benzyl-4-fluoropyrrolidin-3-amine Utilizing a Burgess-Type Transformation
Widlicka, Daniel W.,Gontcharov, Alexander,Mehta, Ruchi,Pedro, Dylan J.,North, Robert
, p. 1970 - 1978 (2019/08/22)
Manufacture of an EGFR inhibitor required the asymmetric synthesis of a key 3,4-trans-substituted pyrrolidine suitable for pilot-plant scale. The initial synthetic route utilized reagents and intermediates that posed safety concerns due to their energetic potential and then required supercritical fluid chromatography to access the desired single enantiomer. Burgess-type reagents provide tremendous utility in organic synthesis but see limited use on large scales because of their high cost and instability. Nevertheless, extensive process development led to a scale-friendly process where in situ formation of a Boc-Burgess reagent enabled access to a chiral cyclic sulfamate from inexpensive materials. ReactIR monitoring was used to study intermediate stability and enabled processing on a multikilogram scale. The sulfamate was converted to trans-3-fluoro-4-aminopyrrolidine 1 with complete stereospecificity. Intermediate crystallinity offered purity control points where byproducts and impurities were rejected, avoiding the need for chromatography.
Compound JK-03M having higher protein kinase G inhibitory activity or pharmaceutically acceptable salt thereof and preparation method thereof
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Paragraph 0093; 0118; 0120-0122, (2018/11/03)
The invention discloses a compound which has higher protein kinase G inhibitory activity and is shown in a formula I or pharmaceutically acceptable salt thereof and a preparation method thereof. The compound JK-03M having the higher protein kinase G inhibitory activity comprises a pharmaceutical composition of a new compound and application of the new compound in treatment of pain, in particular to chronic pain. The formula (1) is shown in the description.
Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines
Kasturi, Sivaprasad,Surarapu, Sujatha,Uppalanchi, Srinivas,Anireddy, Jaya Shree,Dwivedi, Shubham,Anantaraju, Hasitha Shilpa,Perumal, Yogeeswari,Sigalapalli, Dilep Kumar,Babu, Bathini Nagendra,Ethiraj, Krishna S.
supporting information, p. 2818 - 2823 (2017/05/29)
A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH2 group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
Novel PTP1B enzyme inhibitor, preparation method and applications thereof
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Paragraph 0083; 0182-0183, (2017/08/31)
The present invention provides a novel PTP1B enzyme inhibitor, a preparation method and applications thereof, and particularly discloses a class of bis 2-substituted ethylene sulfonate compounds and a preparation method thereof, and uses of the bis 2-substituted ethylene sulfonate compounds as the PTP1B enzyme activity inhibitor. According to the present invention, the prepared novel compound has good PTP1B enzyme activity inhibition effect, and has the application value in preparation of drugs for treatment and prevention of diabetes and obesity.
Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis
Patrick, Donald A.,Gillespie, J. Robert,McQueen, Joshua,Hulverson, Matthew A.,Ranade, Ranae M.,Creason, Sharon A.,Herbst, Zackary M.,Gelb, Michael H.,Buckner, Frederick S.,Tidwell, Richard R.
supporting information, p. 957 - 971 (2017/02/19)
A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24, 2451-2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
Diastereoselective ritter-like reaction on cyclic trifluoromethylated N,O-acetals derived from L-tartaric acid
Jamaa, Abdelkhalek Ben,Grellepois, Fabienne
, p. 10360 - 10375 (2018/05/31)
Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic α-trifluoromethylated N-acyliminium ions were successfully generated from fluorinated O-acetyl-N,O-acetal L-tartaric acid derivatives. The addition of nitriles on these intermediates occurred with high to excellent syn diastereoselectivity and led, in most cases, to oxazolines and amides as single diastereomers. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives, bearing the fluorinated substituent on a tetrasubstituted carbon.
