64896-36-2Relevant academic research and scientific papers
Protein Modification at Tyrosine with Iminoxyl Radicals
Ishiyama, Takashi,Kanai, Motomu,Maruyama, Katsuya,Oisaki, Kounosuke,Sakai, Kentaro,Seki, Yohei,Togo, Takaya
supporting information, p. 19844 - 19855 (2021/11/30)
Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with 1o, and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with 1o to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds
Fuller, Amelia A.,Dounay, Amy B.,Schirch, Douglas,Rivera, Daniel G.,Hansford, Karl A.,Elliott, Alysha G.,Zuegg, Johannes,Cooper, Matthew A,Blaskovich, Mark A. T.,Hitchens, Jacob R.,Burris-Hiday, Sarah,Tenorio, Kristiana,Mendez, Yanira,Samaritoni, J. Geno,O'Donnell, Martin J.,Scott, William L.
, p. 3187 - 3196 (2020/12/21)
New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.
GRANZYME B DIRECTED IMAGING AND THERAPY
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Page/Page column 82; 99, (2019/09/04)
Provided herein are heterocyclic compounds useful for imaging Granzyme B. Methods of imaging Granzyme B, combination therapies, and kits comprising the Granzyme B imaging agents are also provided.
Design, synthesis and evaluation of novel phenyl propionamide derivatives as non-nucleoside hepatitis B virus inhibitors
Qiu, Jingying,Gong, Qineng,Gao, Jian,Chen, Wang,Zhang, Yinpeng,Gu, Xiaoke,Tang, Daoquan
, p. 424 - 434 (2018/01/01)
As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 μM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.
Efficient Synthesis of Glycosylated Matijin-Su Derivatives via Ultrasonic Irradiation
Liang, Guangping,Hu, Zhanxing,Yuan, Jie,Liang, Guangyi,Xu, Bixue
, p. 1353 - 1359 (2016/12/27)
Matijin-Su (1) is a phenylalanine dipeptide compound with anti-hepatitis B virus (HBV) activity. Previous reports suggest that the synthesis of glycosylated Matijin-Su derivatives needs at least 10 steps. To simplify the synthetic procedure, we have developed a shorter and more efficient method for the preparation via ultrasound irradiation. Two galactopyranosylated (2) and two glucopyranosylated (3) derivatives were synthesized in 6 or 7 steps. The overall yields for the total synthesis of galactopyranosylated derivatives were markedly increased to 39% (2a) or 22% (2b). And the yields for glucopyranosylated derivatives also reached 29% (3a) or 16% (3b).
Synthesis and Biological Evaluation of Matijin-Su Derivatives as Potential Antihepatitis B Virus and Anticancer Agents
Qiu, Jingying,Xu, Bixue,Gong, Qineng,Pan, Weidong,Liu, Changxiao,Huang, Zhengming,Gu, Xiaoke,Liang, Guangyi
, p. 1584 - 1592 (2016/11/22)
A series of Matijin-Su (MTS, (2S)-2-{[(2S)-2-benzamido-3-phenylpropanoyl]amino}-3-phenylpropyl acetate) derivatives were synthesized and evaluated for their anti-HBV and cytotoxic activities in?vitro. Six compounds (4g, 4j, 5c, 5g, 5h and 5i) showed signi
Synthesis and anti-tumor activity evaluation of Matijin-Su derivatives
Xu, Bixue,Wang, Ning,Pan, Weidong,Qiu, Jingying,Cao, Peixue,Zhu, Meifen,Feng, Yibin,Liang, Guangyi
, p. 34 - 40 (2014/06/24)
A series of Matijin-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l- phenylalanol) derivatives was synthesized and evaluated for their anti-tumor activities in hepatocellular carcinoma cells. The IC50 of compounds 1, 3, 4, 11, 13 were less than 20 μM, and compound 1 and 3 showed an IC 50 value of less than 9 μM. Expansion inhibition could be found significantly in compound 1 and 3-treated human hepatoma cell HepG2 and PLC/PRF/5, while both compounds exhibit lower toxicity to human hepatocyte cell line L-02. Compound 1 and 3 could induce cell cycle arrest at G1/S phase. This may be attributed to increase level of intracellular reactive oxygen species (ROS). Up-regulation of p38 MAPK activity in responding the ROS stabilize p53 and activate p21 transcription, the critical regulatory in G1/S checkpoint. Observations in this study shed light on the potential of MTS derivatives compound 1 and 3 as novel suppressors to human liver cancer.
Development of a practical and scalable synthesis of anti-HBV drug Y101
Hu, Zhan-Xing,Zhang, Yan-Gong,An, Qiao,Xu, Bi-Xue,Pan, Wei-Dong,Cao, Pei-Xue,Liu, Chang-Xiao,Huang, Zheng-Ming,Xia, Wen,Qiu, Jing-Ying,Liang, Guang-Yi
, p. 9592 - 9600 (2015/01/08)
The process research and development of a practical and scalable synthetic method towards Anti-HBV Drug N-[N-benzoyl-O-(2-dimethylaminoethyl)-l-tyrosyl]-l-phenylalaninol (Y101) was described. Initial synthetic routes of Y101 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the collaboration between Medicinal Chemistry and Research active pharmaceutical ingredient (API), a fit for purpose route for the kilo scale synthesis of Y101 was developed. In contrast, the improved route described here did not require purification by column chromatography for all steps, and the formation of impurities was effectively suppressed. This highly efficient and scalable process was successfully demonstrated in the large-scale synthesis of Y101.
Site-selective chemical modification of chymotrypsin using a peptidyl diphenyl 1-amino-2-phenylethylphosphonate derivative
Ono, Shin,Murai, Junya,Nakai, Takahiko,Kuroda, Hirofumi,Horino, Yoshikazu,Yoshimura, Toshiaki,Oyama, Hiroshi,Umezaki, Masahito
supporting information, p. 860 - 862 (2013/09/02)
For site-selective chemical modification in the vicinity of the active site of chymotrypsin (Csin), a peptide derivative 1 bearing a diphenyl 1-amino-2-phenylethylphosphonate moiety for targeting the active site and an active ester moiety for anchoring to
Strategy for sensor based on fluorescence emission red shift of conjugated polymers: Applications in pH response and enzyme activity detection
Tang, Yanli,Liu, Yue,Cao, Ali
, p. 825 - 830 (2013/03/14)
A new strategy was developed and applied in monitoring pH response and enzyme activity based on fluorescence emission red shift (FERS) of the conjugated polymer PPP-OR10 induced by the inner filter effect (IFE) of nitrobenzene derivatives. Neutral poly(p-
