55114-30-2Relevant academic research and scientific papers
Nickel-Catalyzed Benzylic Substitution of Benzyl Esters with Malonates as a Soft Carbon Nucleophile
Tsuji, Hiroaki,Hashimoto, Keisuke,Kawatsura, Motoi
, p. 8837 - 8841 (2019/11/11)
The nickel-catalyzed benzylic substitution of benzyl alcohol derivatives with a soft carbon nucleophile is extremely rare compared to that with a hard carbon nucleophile. We have achieved the nickel-catalyzed benzylic substitution of benzyl esters with malonates as a soft carbon nucleophile. Primary and secondary benzyl 2,3,4,5,6-pentafluorobenzoates as well as a wide variety of malonate derivatives were well tolerated in the nickel-catalyzed reaction, providing the corresponding alkylation products in 46-86% yields (34 examples). Additionally, we propose a possible reaction mechanism that would undergo via the ??1- A nd ??3-benzylnickel intermediates.
Trideuteromethylation Enabled by a Sulfoxonium Metathesis Reaction
Shen, Zuyuan,Zhang, Shilei,Geng, Huihui,Wang, Jiarui,Zhang, Xinyu,Zhou, Anqi,Yao, Cheng,Chen, Xiaobei,Wang, Wei
supporting information, p. 448 - 452 (2019/01/14)
A conceptually novel sulfoxonium metathesis reaction between TMSOI and cost-effective DMSO-d6 is developed for the efficient generation of a new trideuteromethylation reagent TDMSOI. The new reagent TDMSOI is produced highly efficiently by simply heating a mixture of TMSOI and DMSO-d6 and directly used for subsequent trideuteromethylation in a "one-pot" operation. The preparative power of the new versatile reagent and the "one-pot" protocol is demonstrated by its use to install the ?CD3 moiety into broad functionalities including phenols, thiophenols, acidic amines, and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).
Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox
Hermant, Paul,Bosc, Damien,Piveteau, Catherine,Gealageas, Ronan,Lam, Baovy,Ronco, Cyril,Roignant, Matthieu,Tolojanahary, Hasina,Jean, Ludovic,Renard, Pierre-Yves,Lemdani, Mohamed,Bourotte, Marilyne,Herledan, Adrien,Bedart, Corentin,Biela, Alexandre,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 9067 - 9089 (2017/11/14)
Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids to explore the structure-plasma stability relationships in these series and to identify which enzyme(s) and which pharmacophores are critical for plasma stability. Arylesterases and carboxylesterases were identified as the main metabolic enzymes for hydroxamic acids. Finally, we suggest structural features to be introduced or removed to improve stability. This work thus provides the first medicinal chemistry toolbox (experimental procedures and structural guidance) to assess and control the plasma stability of hydroxamic acids and realize their full potential as in vivo pharmacological probes and therapeutic agents. This study is particularly relevant to preclinical development as it allows obtaining compounds equally stable in human and rodent models.
COMPOUNDS USEFUL AS MODULATORS OF TRPM8
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Paragraph 0540, (2016/03/29)
The present invention includes compounds useful as modulators of TRPM8, such as compounds of Formulae (Ia), (Ib) and (Ic), and the subgenus and species thereof; personal products containing those compounds; and the use of those compounds and the personal products, particularly the use of increasing or inducing chemesthetic sensations, such as cooling or cold sensations.
An improved solvent-free system for the microwave-assisted decarboxylation of malonate derivatives based on the use of imidazole
Tellitu, Imanol,Beitia, Itziar,Díaz, Marta,Alonso, Argi?e,Moreno, Isabel,Domínguez, Esther
, p. 8251 - 8255 (2015/10/05)
A comparative study of the thermal and microwave-assisted decarboxylation of a series of mono- and disubstituted monohydrolyzed malonate derivatives has been carried out. It has been found out that in both circumstances the use of imidazole has a profound effect on the success of the reaction. In general terms the assistance of microwave irradiation accelerates the decarboxylation process significantly and, at the same time, permits the use of minored temperatures with respect to the thermal via. It has been also found that both the thermal and the microwave-assisted transformation can be developed under solvent-free conditions.
Design of bisquinolinyl malonamides as Zn2+ ion-selective fluoroionophores based on the substituent effect
Moriuchi-Kawakami, Takayo,Kawata, Keita,Nakamura, Sho,Koyama, Yoshiaki,Shibutani, Yasuhiko
, p. 9805 - 9813 (2015/01/09)
A series of malonamides possessing two quinoline moieties were synthesized and characterized as fluoroionophores for the Zn2+ ion. We focused on the relationship between the substituents introduced to the C2-position of the malonamides and their Zn2+ ion-selectivity, exploiting the structural effect of the substituents in the design of the fluoroionophores with high selectivity. The substituents introduced to the malonamides were the methyl, benzyl and naphthalenylmethyl groups. In dimethyl sulfoxide solvent, all substituted bisquinolinyl malonamides showed excellent fluorescence sensing for the Zn2+ ion, while unsubstituted bisquinolinyl malonamide 1 displayed ratiometric sensing for the Co2+ ion. N,N′-Bis(8-quinolyl)-2-methyl-2-naphthalenylmethyl malonamide 4 exhibited the highest Zn2+ ion-selectivity against the Cd2+ ion. Although the substituents introduced into the C2-position are spatially distant from the quinoline recognition moiety, this study indicated that they greatly influenced the ion selectivities of the bisquinolinyl malonamides. Furthermore, it was demonstrated that visible fluorescence analyses could be performed on malonamide 4.
Structure-activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors
Deprez-Poulain, Rebecca,Flipo, Marion,Piveteau, Catherine,Leroux, Florence,Dassonneville, Sandrine,Florent, Isabelle,Maes, Louis,Cos, Paul,Deprez, Benoit
, p. 10909 - 10917 (2013/03/14)
Malaria is a severe infectious disease that causes between 655 000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has
Hydroxamates: Relationships between structure and plasma stability
Flipo, Marion,Charton, Julie,Hocine, Akila,Dassonneville, Sandrine,Deprez, Benoit,Deprez-Poulain, Rebecca
experimental part, p. 6790 - 6802 (2010/04/04)
Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of selectivity, toxicity, or poor stability. To help medicinal chemists with respect to plasma stability, we have performed the first and preliminary study on structure-plasma stability for hydroxamates. We define some structural rules to predict or improve the plasma stability in the preclinical stage.
Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysis
Harabe, Tetsuji,Matsumoto, Takatoshi,Shioiri, Takayuki
experimental part, p. 4044 - 4052 (2009/10/02)
The carbomethoxy group at the C2 position of the 2,5-multisubstituted 1,3-dioxanes prefers the axial conformation rather than the equatorial one due to an anomeric effect. The trans isomers of the 5-monosubstituted compounds are more selectively hydrolyzed than the cis isomers. Based on the calculated results, hydrolysis to the trans isomers is attributed to the larger carbonyl charges of the trans than those of the cis isomers. The anomeric and homoanomeric effects will explain the axial preference of the carbomethoxy group and selective hydrolysis to the trans isomers. Furthermore, the calculated stability between the cis and trans isomers is in good agreement with the experimental results in the equilibrium state.
Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT 6 receptor ligands
Alcalde, Ermitas,Mesquida, Neus,Frigola, Jordi,Lopez-Perez, Sara,Merce, Ramon
experimental part, p. 3795 - 3810 (2009/02/04)
A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT6 receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/ isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides 13-17 using an optimized procedure with AlH 3-NMe2Et. The binding at the 5-HT6 receptor was with moderate affinity (Ki = 216.5 nM) for the (Z)- benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenylsulfonamide counterpart 13 (Ki = 50.6 nM). Selected indenylsulfonamides 14-17 were then tested, showing Ki values as low as 20.2 nM. The Royal Society of Chemistry 2008.
