- Self-assembly of Fluorescent Dehydroberberine Enhances Mitochondria-Dependent Antitumor Efficacy
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Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria-targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH-BBR), as a new mitochondria-targeting probe capable of self-assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X-ray crystallography revealed that the self-assembly process was attributed to a synergy of different molecular interactions, including π–π stacking, O???π interaction and electrostatic interaction between DH-BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH-BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self-assembly and tune antitumor activity of mitochondria-targeting probes, which can facilitate to improve cancer treatment in vivo.
- An, Ruibing,Gu, Zhanni,Sun, Haifeng,Hu, Yuxuan,Yan, Runqi,Ye, Deju,Liu, Hong
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supporting information
p. 9812 - 9819
(2018/07/25)
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- Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans
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We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole-resistant Candida albicans. A structure-activity relationship study of 95 analogues led us to identify the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2- (substituted phenyl)acetamides 7 a-l, which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N-(2-(benzo[d][1,3]dioxol- 5-yl)ethyl)-2-(2-fluorophenyl)acetamide) significantly decreased the MIC 80 values of fluconazole from 128.0 μg mL-1 to 0.5 μg mL-1 against fluconazole-resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells. Build it better: Structural optimization of berberine led to the identification of the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl) ethyl)-2-(substituted phenyl)acetamides 7 a-l, which exhibited remarkable in vitro synergistic antifungal activity against fluconazole-resistant Candida albicans in combination with fluconazole. Compound 7 d exhibited much lower cytotoxicity than berberine toward human umbilical vein endothelial cells. Copyright
- Liu, Hong,Wang, Liang,Li, Yan,Liu, Jiang,An, Maomao,Zhu, Shaolong,Cao, Yongbing,Jiang, Zhihui,Zhao, Mingzhu,Cai, Zhan,Dai, Li,Ni, Tingjunhong,Liu, Wei,Chen, Simin,Wei, Changqing,Zang, Chengxu,Tian, Shujuan,Yang, Jingyu,Wu, Chunfu,Zhang, Dazhi,Liu, Hua,Jiang, Yuanying
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p. 207 - 216
(2014/01/17)
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- Mechanistic and structural analysis of Drosophila melanogaster arylalkylamine N-acetyltransferases
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(Chemical Equation Presented). Arylalkylamine N-acetyltransferase (AANAT) catalyzes the penultimate step in the biosynthesis of melatonin and other N-acetylarylalkylamides from the corresponding arylalkylamine and acetyl-CoA. The N-acetylation of arylalkylamines is a critical step in Drosophila melanogaster for the inactivation of the bioactive amines and the sclerotization of the cuticle. Two AANAT variants (AANATA and AANATB) have been identified in D. melanogaster , in which AANATA differs from AANATB by the truncation of 35 amino acids from the N-terminus. We have expressed and purified both D. melanogaster AANAT variants (AANATA and AANATB) in Escherichia coli and used the purified enzymes to demonstrate that this N-terminal truncation does not affect the activity of the enzyme. Subsequent characterization of the kinetic and chemical mechanism of AANATA identified an ordered sequential mechanism, with acetyl-CoA binding first, followed by tyramine. We used a combination of pH-activity profiling and site-directed mutagenesis to study prospective residues believed to function in AANATA catalysis. These data led to an assignment of Glu-47 as the general base in catalysis with an apparent pKa of 7.0. Using the data generated for the kinetic mechanism, structure-function relationships, pH-rate profiles, and site-directed mutagenesis, we propose a chemical mechanism for AANATA.
- Dempsey, Daniel R.,Jeffries, Kristen A.,Bond, Jason D.,Carpenter, Anne-Marie,Rodriguez-Ospina, Santiago,Breydo, Leonid,Caswell, K. Kenneth,Merkler, David J.
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p. 7777 - 7793
(2015/02/19)
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- Transformation of oximes of phenetyl ketone derivatives to quinolines and azaspirotrienones catalyzed by tetrabutylammonium perrhenate and trifluoromethanesulfonic acid
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Phenethyl ketone oximes are converted to quinolines by the treatment with tetrabutylammonium perrhenate, trifluoromethanesulfonic acid, and chloranil in refluxing 1,2-dichloroethane. Azaspirotrienones can be synthesized from p-hydroxyphenethyl or 3-(p-hydroxyphenyl)propyl ketone oximes by applying the above method. Thus prepared azaspirotrienones are converted to quinolines by acid treatment.
- Kusama,Yamashita,Uchiyama,Narasaka
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p. 965 - 975
(2007/10/03)
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- The E.S.R. Spectra of Cation Radicals Derived from Phenethyltetrahydroisoquinoline Ethers and Model Compounds
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Cation radicals derived from the title compounds by oxidation with thallium tristrifluoroacetate have been characterized.The structures assigned to these radicals suggest that initial oxidation occures at the phenethyl ring in the compounds examined.Oxidation of homolaudanosine in this way gave the expected homoaporphine.
- Hewgill, Frank R.,Pass, Michael C.
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p. 555 - 563
(2007/10/02)
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