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Tadahisa Iwata - One of the best experts on this subject based on the ideXlab platform.
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synthesis and characterization of regioselectively substituted curdlan hetero esters with different ester Groups on primary and secondary hydroxyl Groups
Carbohydrate Polymers, 2018Co-Authors: Chihying Chien, Tadahisa IwataAbstract:Abstract Two kinds of regioselectively substituted curdlan hetero ester, 2,4-di- O -acetyl-6- O -propionyl-curdlan (CD24Ac6Pr) and 2,4-di- O -propionyl-6- O -acetyl-curdlan (CD24Pr6Ac), were synthesized. By repeating deTritylation and esterification, a new method to remove Trityl Group from 6- O -Trityl-curdlan without acyl migration was developed. Their molecular structures, thermal and mechanical properties and crystal structures were analyzed by NMR, TGA, DSC, tensile test and WAXD. It was concluded that the ester Groups substituted on secondary hydroxyl Groups at C2 and C4 positions play the decisive role in the melting behavior and crystalline formation of curdlan esters. Also, the mechanical properties of curdlan esters are controllable by the adjustment on its molecular structures.
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synthesis and characterization of regioselectively substituted curdlan hetero esters via an unexpected acyl migration
Carbohydrate Polymers, 2017Co-Authors: Chihying Chien, Yukiko Enomotorogers, Akio Takemura, Tadahisa IwataAbstract:Abstract Regioselectively substituted curdlan esters were synthesized by protecting the C6 primary hydroxyl Group with a triphenylmethyl Group followed by the acylation of the secondary hydroxyl Groups at C2 and C4. The subsequent deTritylation of C6 Trityl Group under acidic conditions revealed an unexpected acyl migration from C4 to C6. This unique acyl migration in curdlan was first observed, which haven⿿t been reported in other polysaccharides such as cellulose. The rate of this migration was found to be dependent on the length of the acyl Group, leading to the proposal of a new mechanism for this transformation. Based on these results, we synthesized 2,6-di-O-acetyl-4-O-propionyl-curdlan, which was fully characterized by 1H NMR, 13C NMR, COSY, HSQC and HMBC analyses. Thermogravimetric analysis and differential scanning calorimetry measurements revealed that the regioselective esterification to curdlan promoted its crystallization compared with randomly mixed ester derivatives.
Herbert Mayr - One of the best experts on this subject based on the ideXlab platform.
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structures and reactivities of 2 Trityl and 2 triphenylsilyl pyrrolidine derived enamines evidence for negative hyperconjugation with the Trityl Group
Journal of the American Chemical Society, 2014Co-Authors: Hannes Erdmann, Peter Mayer, Armin R Ofial, Sami Lakhdar, Herbert MayrAbstract:X-ray structures of enamines and iminium ions derived from 2-Tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine (Bolm–Christmann–Strohmann catalyst) have been determined. Kinetic investigations showed that enamines derived from phenylacetaldehyde and pyrrolidine (R = H) or 2-(triphenylsilyl)pyrrolidine (R = SiPh3) have similar reactivities toward benzhydryl cations Ar2CH+ (reference electrophiles), while the corresponding enamine derived from 2-Tritylpyrrolidine (R = CPh3) is 26 times less reactive. The rationalization of this phenomenon by negative hyperconjugative interaction of the Trityl Group with the lone pair of the enamine nitrogen is supported by the finding that the Trityl Group in the 2-position of the pyrrolidine increases the electrophilic reactivity of iminium ions derived from cinnamaldehyde by a factor of 14. The consequences of these observations for the rationalization of the reactivity of the Jorgensen–Hayashi catalyst (diphenylprolinol trimethylsilyl ether) are disc...
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Structures and Reactivities of 2‑Trityl- and 2‑(Triphenylsilyl)pyrrolidine-Derived Enamines: Evidence for Negative Hyperconjugation with the Trityl Group
2014Co-Authors: Hannes Erdmann, Peter Mayer, Armin R Ofial, Sami Lakhdar, Herbert MayrAbstract:X-ray structures of enamines and iminium ions derived from 2-Tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine (Bolm–Christmann–Strohmann catalyst) have been determined. Kinetic investigations showed that enamines derived from phenylacetaldehyde and pyrrolidine (R = H) or 2-(triphenylsilyl)pyrrolidine (R = SiPh3) have similar reactivities toward benzhydryl cations Ar2CH+ (reference electrophiles), while the corresponding enamine derived from 2-Tritylpyrrolidine (R = CPh3) is 26 times less reactive. The rationalization of this phenomenon by negative hyperconjugative interaction of the Trityl Group with the lone pair of the enamine nitrogen is supported by the finding that the Trityl Group in the 2-position of the pyrrolidine increases the electrophilic reactivity of iminium ions derived from cinnamaldehyde by a factor of 14. The consequences of these observations for the rationalization of the reactivity of the Jørgensen–Hayashi catalyst (diphenylprolinol trimethylsilyl ether) are discussed
Chihying Chien - One of the best experts on this subject based on the ideXlab platform.
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synthesis and characterization of regioselectively substituted curdlan hetero esters with different ester Groups on primary and secondary hydroxyl Groups
Carbohydrate Polymers, 2018Co-Authors: Chihying Chien, Tadahisa IwataAbstract:Abstract Two kinds of regioselectively substituted curdlan hetero ester, 2,4-di- O -acetyl-6- O -propionyl-curdlan (CD24Ac6Pr) and 2,4-di- O -propionyl-6- O -acetyl-curdlan (CD24Pr6Ac), were synthesized. By repeating deTritylation and esterification, a new method to remove Trityl Group from 6- O -Trityl-curdlan without acyl migration was developed. Their molecular structures, thermal and mechanical properties and crystal structures were analyzed by NMR, TGA, DSC, tensile test and WAXD. It was concluded that the ester Groups substituted on secondary hydroxyl Groups at C2 and C4 positions play the decisive role in the melting behavior and crystalline formation of curdlan esters. Also, the mechanical properties of curdlan esters are controllable by the adjustment on its molecular structures.
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synthesis and characterization of regioselectively substituted curdlan hetero esters via an unexpected acyl migration
Carbohydrate Polymers, 2017Co-Authors: Chihying Chien, Yukiko Enomotorogers, Akio Takemura, Tadahisa IwataAbstract:Abstract Regioselectively substituted curdlan esters were synthesized by protecting the C6 primary hydroxyl Group with a triphenylmethyl Group followed by the acylation of the secondary hydroxyl Groups at C2 and C4. The subsequent deTritylation of C6 Trityl Group under acidic conditions revealed an unexpected acyl migration from C4 to C6. This unique acyl migration in curdlan was first observed, which haven⿿t been reported in other polysaccharides such as cellulose. The rate of this migration was found to be dependent on the length of the acyl Group, leading to the proposal of a new mechanism for this transformation. Based on these results, we synthesized 2,6-di-O-acetyl-4-O-propionyl-curdlan, which was fully characterized by 1H NMR, 13C NMR, COSY, HSQC and HMBC analyses. Thermogravimetric analysis and differential scanning calorimetry measurements revealed that the regioselective esterification to curdlan promoted its crystallization compared with randomly mixed ester derivatives.
Hannes Erdmann - One of the best experts on this subject based on the ideXlab platform.
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structures and reactivities of 2 Trityl and 2 triphenylsilyl pyrrolidine derived enamines evidence for negative hyperconjugation with the Trityl Group
Journal of the American Chemical Society, 2014Co-Authors: Hannes Erdmann, Peter Mayer, Armin R Ofial, Sami Lakhdar, Herbert MayrAbstract:X-ray structures of enamines and iminium ions derived from 2-Tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine (Bolm–Christmann–Strohmann catalyst) have been determined. Kinetic investigations showed that enamines derived from phenylacetaldehyde and pyrrolidine (R = H) or 2-(triphenylsilyl)pyrrolidine (R = SiPh3) have similar reactivities toward benzhydryl cations Ar2CH+ (reference electrophiles), while the corresponding enamine derived from 2-Tritylpyrrolidine (R = CPh3) is 26 times less reactive. The rationalization of this phenomenon by negative hyperconjugative interaction of the Trityl Group with the lone pair of the enamine nitrogen is supported by the finding that the Trityl Group in the 2-position of the pyrrolidine increases the electrophilic reactivity of iminium ions derived from cinnamaldehyde by a factor of 14. The consequences of these observations for the rationalization of the reactivity of the Jorgensen–Hayashi catalyst (diphenylprolinol trimethylsilyl ether) are disc...
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Structures and Reactivities of 2‑Trityl- and 2‑(Triphenylsilyl)pyrrolidine-Derived Enamines: Evidence for Negative Hyperconjugation with the Trityl Group
2014Co-Authors: Hannes Erdmann, Peter Mayer, Armin R Ofial, Sami Lakhdar, Herbert MayrAbstract:X-ray structures of enamines and iminium ions derived from 2-Tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine (Bolm–Christmann–Strohmann catalyst) have been determined. Kinetic investigations showed that enamines derived from phenylacetaldehyde and pyrrolidine (R = H) or 2-(triphenylsilyl)pyrrolidine (R = SiPh3) have similar reactivities toward benzhydryl cations Ar2CH+ (reference electrophiles), while the corresponding enamine derived from 2-Tritylpyrrolidine (R = CPh3) is 26 times less reactive. The rationalization of this phenomenon by negative hyperconjugative interaction of the Trityl Group with the lone pair of the enamine nitrogen is supported by the finding that the Trityl Group in the 2-position of the pyrrolidine increases the electrophilic reactivity of iminium ions derived from cinnamaldehyde by a factor of 14. The consequences of these observations for the rationalization of the reactivity of the Jørgensen–Hayashi catalyst (diphenylprolinol trimethylsilyl ether) are discussed
Maria Jesus Perezperez - One of the best experts on this subject based on the ideXlab platform.
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5 o Tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase
Journal of Medicinal Chemistry, 2006Co-Authors: Elena Casanova, Anaisabel Hernandez, Mariajose Camarasa, Sandra Liekens, Jan Balzarini, Evamaria Priego, Maria Jesus PerezperezAbstract:On the basis of our previous findings that 5‘-O-Tritylinosine (KIN59) behaves as an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken the synthesis and enzymatic evaluation of a novel series of nucleoside analogues modified at positions 1, 2, or 6 of the purine ring and at the 5‘-position of the ribose moiety of the lead compound KIN59. SAR studies indicate that quite large structural variations can be performed on KIN59 without compromising TPase inhibition. Thus, incorporation of a cyclopropylmethyl or a cyclohexylmethyl Group at position N1 of 5‘-O-Tritylinosine increases the inhibitory activity against TPase 10-fold compared to KIN59. Moreover, the Trityl Group at the 5‘-position of the ribose seems to be crucial for TPase inhibition. The here reported results further substantiate that 5‘-O-Trityl nucleosides represent a new class of TPase inhibitors that should be further explored in those biological systems where TPase plays an instrumental role (i.e. ...
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5 o Tritylated nucleoside derivatives inhibition of thymidine phosphorylase and angiogenesis
Molecular Pharmacology, 2006Co-Authors: Sandra Liekens, Anaisabel Hernandez, Mariajose Camarasa, Maria Jesus Perezperez, Annelies Bronckaers, Evamaria Priego, Elena Casanova, Jan BalzariniAbstract:Thymidine phosphorylase (TPase) is one of the key enzymes involved in the pyrimidine nucleoside salvage pathway. However, TPase also stimulates angiogenesis, and its expression correlates well with microvessel density and metastasis in a variety of human tumors. We have shown recently that 5′- O -Trityl-inosine (KIN59) allosterically inhibits TPase enzymatic activity. KIN59 also inhibits TPase-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. The Trityl Group was found to be instrumental to preserve both the anti-TPase and antiangiogenic effect. We have now synthesized a variety of novel 5′- O -Trityl nucleoside derivatives. Enzyme activity studies showed that the anti-TPase activity is significantly improved by replacement of the hypoxanthine base by thymine [3.5-fold; i.e., 5′- O -Tritylthymidine (KIN6)] and the introduction of chloride on the Trityl Group [7-fold; i.e., 5′- O -(4-chloroTrityl)-inosine (TP136)], whereas removal of 2′-hydroxyl in the ribose did not significantly alter the anti-TPase activity. Enzyme kinetic studies also demonstrated that 1-(5′- O -Trityl-β-d-ribofuranosyl)-thymine (TP124), like KIN59, inhibits TPase in a noncompetitive fashion both with respect to phosphate and thymidine. Most KIN59 analogs markedly inhibited TPase-induced angiogenesis in the CAM assay. In vitro studies showed that the antiangiogenic effect of these compounds is not attributed to endothelial cell toxicity. For several compounds, there was no stringent correlation between their anti-TPase and antiangiogenic activity, indicating that these compounds may also act on other angiogenesis mediators. The antiangiogenic 5′- O -Trityl nucleoside analogs also caused degradation of pre-existing, immature vessels at the site of drug exposure. Thus, 5′- O -Trityl nucleoside derivatives combine antiangiogenic and vascular-targeting activities, which opens perspectives for their potential use as anticancer agents.
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the nucleoside derivative 5 o Trityl inosine kin59 suppresses thymidine phosphorylase triggered angiogenesis via a noncompetitive mechanism of action
Journal of Biological Chemistry, 2004Co-Authors: Sandra Liekens, Anaisabel Hernandez, Mariajose Camarasa, Domenico Ribatti, Maria Jesus PerezperezAbstract:Abstract Thymidine phosphorylase (TPase) catalyzes the reversible phosphorolysis of pyrimidine deoxynucleosides to 2-deoxy-d-ribose-1-phosphate and their respective pyrimidine bases. The enzymatic activity of TPase was found to be essential for its angiogenesis-stimulating properties. All of the previously described TPase inhibitors are either pyrimidine analogues that interact with the nucleoside-binding site of the enzyme or modified purine derivatives that mimic the pyrimidine structure and either compete with thymidine or act as a multisubstrate (competitive) inhibitor. We now describe the inhibitory activity of the purine riboside derivative KIN59 (5′-O-Tritylinosine) against human and bacterial recombinant TPase and TPase-induced angiogenesis. In contrast to previously described TPase inhibitors, KIN59 does not compete with the pyrimidine nucleoside or the phosphate-binding site of the enzyme but noncompetitively inhibits TPase when thymidine or phosphate is used as the variable substrate. In addition, KIN59 was far more active than other TPase inhibitors, previously tested by us, against TPase-induced angiogenesis in the chorioallantoic membrane assay. The observed anti-angiogenic effect of KIN59 was not accompanied by inflammation or any visible toxicity. Inosine did not inhibit the enzymatic or angiogenic activity of the enzyme, indicating that the 5′-O-Trityl Group in KIN59 is essential for the observed effects. In contrast with current concepts, our data indicate that the angiogenic activity of TPase is not solely directed through its functional nucleoside and phosphate-binding sites. Other regulatory (allosteric) site(s) in TPase may play an important role in the mechanism of TPase-triggered angiogenesis stimulation and apoptosis inhibition. Identification of these site(s) is important to obtain a better insight into the molecular role of TPase in the progression of cancer and angiogenic diseases.
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acyclic nucleoside analogues as novel inhibitors of human mitochondrial thymidine kinase
Journal of Medicinal Chemistry, 2002Co-Authors: Anaisabel Hernandez, Mariajose Camarasa, Jan Balzarini, Anna Karlsson, Maria Jesus PerezperezAbstract:A series of acyclic nucleoside analogues of 5‘-O-Tritylthymidine have been synthesized and evaluated as potential human mitochondrial thymidine kinase (TK-2) inhibitors. In this series, the sugar moiety of the parent 5‘-O-Tritylthymidine has been replaced by aliphatic chains including (E)- and (Z)-butenol, butynol, or butanol. Among them the (Z)-butenyl derivative (10) showed an IC50 against TK-2 of 1.5 μM, being 1 order of magnitude more potent than the parent 5‘-O-Tritylthymidine. This lead compound has been further modified by replacing the thymine base by other pyrimidine bases such as 5-iodouracil, 5-ethyluracil, 5-methylcytosine, 3-N-methylthymine, or 5,6-dihydrothymine, as well as by the purine base guanine. The Trityl Group has also been replaced by different aliphatic and aromatic acyl moieties including tert-butylacetyl, hexanoyl, decanoyl, and diphenylacetyl moieties. The evaluation of the compounds against TK-2 and the phylogenetically close HSV-1 TK has shown that the base moiety plays a cruc...
