158671-29-5Relevant articles and documents
Synthesis technology of C-Fos/AP-1 inhibitor
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Paragraph 0071; 0077; 0078; 0079; 0080, (2019/01/08)
The invention belongs to the technical field of pharmaceutical synthesis and especially relates to a synthesis technology of a C-Fos/AP-1 inhibitor. Starting from cheap raw materials 2,4-dimethoxybenzoic acid and 2-methoxyphenylpropionic acid, acid chloride is prepared by using thionyl chloride, and a Friedel-Crafts acylation reaction is carried out under the catalysis of aluminium trichloride soas to obtain a coupled product; then, pyridine hydrobromide and sodium chloride are used to react at 160 DEG C for 30 minutes to complete the demethylation for synthesis of lactonic ring by one step,and the product can be directly used in the next reaction without purification; the cyclopentyl group is introduced by nucleophilic substitution; the lactone ring is opened to form methyl ester; afterpurification, a benzoisoxazolyl group is introduced by nucleophilic substitution, and a protecting group is taken off to prepare the final product T5224. The route of the invention is short, and onlythe Friedel-Crafts acylation, lactone ring opening and introduction of the benzoisoxazolyl group require the step of purification. The cost of the raw materials is low, and the reaction time of the process route is short. The synthesis technology is suitable for industrial production.
Liposomal bortezomib nanoparticles via boronic ester prodrug formulation for improved therapeutic efficacy in vivo
Ashley, Jonathan D.,Stefanick, Jared F.,Schroeder, Valerie A.,Suckow, Mark A.,Kiziltepe, Tanyel,Bilgicer, Basar
, p. 5282 - 5292 (2014/07/08)
In this study, we describe the development of liposomal bortezomib nanoparticles, which was accomplished by synthesizing bortezomib prodrugs with reversible boronic ester bonds and then incorporating the resulting prodrugs into the nanoparticles via surface conjugation. Initially, several prodrug candidates were screened based upon boronic ester stability using isobutylboronic acid as a model boronic acid compound. The two most stable candidates were then selected to create surface conjugated bortezomib prodrugs on the liposomes. Our strategy yielded stable liposomal bortezomib nanoparticles with a narrow size range of 100 nm and with high reproducibility. These liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity against multiple myeloma cell lines in vitro and remarkable tumor growth inhibition with reduced systemic toxicity compared to free bortezomib in vivo. Taken together, this study demonstrates the incorporation of bortezomib into liposomal nanoparticles via reversible boronic ester bond formation to enhance the therapeutic index for improved patient outcome.
Benzimidazolones: A new class of selective peroxisome proliferator- activated receptor γ (PPARγ) modulators
Liu, Weiguo,Lau, Fiona,Liu, Kun,Wood, Harold B.,Zhou, Gaochao,Chen, Yuli,Li, Ying,Akiyama, Taro E.,Castriota, Gino,Einstein, Monica,Wang, Chualin,McCann, Margaret E.,Doebber, Thomas W.,Wu, Margaret,Chang, Ching H.,McNamara, Lesley,McKeever, Brian,Mosley, Ralph T.,Berger, Joel P.,Meinke, Peter T.
supporting information; experimental part, p. 8541 - 8554 (2012/02/04)
A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl) -5-methylox-azolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models. (Figure presented)
