136918-07-5Relevant articles and documents
TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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Paragraph 1547; 1548, (2021/02/12)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
Using DMF as Both a Catalyst and Cosolvent for the Regioselective Silylation of Polyols and Diols
Lv, Jian,Luo, Tao,Zou, Dapeng,Dong, Hai
, p. 6383 - 6395 (2019/11/05)
Highly regioselective silylation of primary hydroxyl groups of unprotected polyols and diols was obtained by the use of a mixed solvent of MeCN/DMF (10:1) in this study. DMF was discovered to be a good catalyst in this reaction, although the silylation us
A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae
Wang, Xu,Zeng, Yuna,Sheng, Li,Larson, Peter,Liu, Xue,Zou, Xiaowen,Wang, Shufang,Guo, Kaijing,Ma, Chen,Zhang, Gang,Cui, Huaqing,Ferguson, David M.,Li, Yan,Zhang, Jingren,Aldrich, Courtney C.
supporting information, p. 2305 - 2332 (2019/04/25)
Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.
