- A stage-specific cancer chemotherapy strategy through flexible combination of reduction-activated charge-conversional core-shell nanoparticles
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Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.
- Han, Lingfei,Wang, Yingming,Huang, Xiaoxian,Liu, Bowen,Hu, Lejian,Ma, Congyu,Liu, Jun,Xue, Jingwei,Qu, Wei,Liu, Fulei,Feng, Feng,Liu, Wenyuan
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- Narciclasine derivative, and preparation and application thereof in preparation of antitumor drugs
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The invention provides a narciclasine derivative represented by the following structural formula I, wherein R1 is alkyl, cycloalkyl, benzyl or substituted benzyl, R2 is alkyl, cycloalkyl, benzyl or substituted benzyl, and n is an integer from 1 to 10. The narciclasine derivative is subjected to a tumor cell toxicity killing effect test, and results prove that the narciclasine derivative has strong toxicity killing effects on lung gland tumor cells, intestinal tumor cells, breast tumor cells, liver tumor cells, prostate tumor cells, melanoma tumor cells, endometrial tumor cells and neuroglia tumor cells, so the narciclasine derivative can be used for preparation of antitumor drugs. The invention provides a preparation method of the narciclasine derivative. The narciclasine derivative has a novel side-chain structure, shows excellent inhibitory activity on a variety of tumor cell strains, has drug efficacy better than that of narciclasine, allows toxic and side effects of the compound to be improved, provides new drugs for treatment of malignant tumors, and is of great clinical application value.
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Paragraph 0079; 0080; 0081
(2017/04/28)
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- Brain targeted prodrug of AMPA receptor synergist and medical purpose thereof
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The invention relates to a compound shown by a general formula I, or an isomer, a medicinal salt and a solvate of the compound. The invention also relates to a composition containing the compound shown by the general formula I, or the isomer, the medicinal salt and the solvate of the compound, and a pharmaceutically acceptable carrier, a shaping agent or a diluent. The invention also relates to the compound shown by the general formula I, or the isomer, the medicinal salt and the solvate of the compound, and a purpose for treating glutamic acid hypofunction diseases, neurodegenerative diseases, respiratory depression diseases or symptoms, particularly the purpose used in diseases or symptoms relevant to AMPA receptors. The formula I is shown in the description.
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Paragraph 0103; 0108; 0109
(2017/11/04)
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- Design, synthesis and biological evaluation of brain-targeted thiamine disulfide prodrugs of ampakine compound LCX001
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: Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.
- Xiao, Dian,Meng, Fan-Hua,Dai, Wei,Yong, Zheng,Liu, Jin-Qiu,Zhou, Xin-Bo,Li, Song
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- Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen
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Glucosyl derivates exhibited favorable distribution to the brain. However, bidirectional transport of glucose transporter 1 might decrease concentrations of the prodrugs in brain before the release of parent drugs. To overcome this defect, glucosyl thiamine disulfide prodrugs 1a-1c incorporating naproxen were designed and synthesized. Furthermore, prodrug 2 and 3 were also prepared as control. The favorable physicochemical properties of these prodrugs were verified by stability and metabolism studies. Results from the in vivo distribution study indicated that 1a-1c, and 1b in particular, significantly increased the level of naproxen in brain when compared to 2 and 3. The study suggested glucosyl thiamine disulfide was a promising carrier to enhance the brain bioavailability of central nervous system active drugs.
- Fan, Wei,Wu, Yong,Li, Xian-Kun,Yao, Nian,Li, Xun,Yu, Yong-Guo,Hai, Li
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experimental part
p. 3651 - 3661
(2011/11/06)
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- Methods of Treating or Preventing Cardiac Disease Associated With a High Fat Diet
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The present invention relates to a method of treating or preventing cardiac disorders, myocardial inflammation or myocardial oxidative stress associated with a high fat diet or in a patient subjected to a high fat diet using the thiazolium compounds and compositions of the invention. The present invention also relates to a method of ameliorating weight gain, myocardial AGE accumulation associated, mitochondrial superoxide production, RAGE expression or PPARα expression with a high fat diet or in a patient subjected to a high fat diet using the thiazolium compounds and compositions of the invention.
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- N-Heterocyclic carbene catalyzed intramolecular nucleophilic addition of carbonyl anion equivalents to enol ethers
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The intramolecular nucleophilic addition reaction of acyl anion equivalents to enol ethers is described, which was catalyzed by N-heterocyclic carbenes generated in situ from readily available thiazolium salt. In this transformation, benzofuranones were obtained in excellent yield. In combination with our previous work, the precise mechanistic elucidation for the formation of benzofuranones has been further investigated. A labeling experiment implied that the transformation proceeds through a nucleophilic addition mechanism.
- He, Jinmei,Tang, Shouchu,Liu, Jian,Su, Yingpeng,Pan, Xinfu,She, Xuegong
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p. 8797 - 8800
(2008/12/21)
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- Method and composition for rejuvenating hair, nails, tissues, cells and organs by ex-vivo or immersive treatment
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A method and composition for the treatment of hair, nail, ex-vivo organ, ex-vivo cell or ex-vivo tissue to improve the biomechanical and diffusional characteristics comprising an effective amount of a compound selected from the group consisting of compounds of the formula
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- Method for treating fibrotic diseases or other indications IC
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Provided, among other things, is a method of treating or ameliorating or preventing an indication of the invention in an animal, including a human comprising administering an effective amount of a compound of the formula I:
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- Preventing and reversing the formation of advanced glycosylation endproducts
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The present invention relates to compositions and methods for inhibiting and reversing nonenzymatic cross-linking (protein aging). Accordingly, compositions are disclosed which comprise an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins, and which additionally reverse pre-formed crosslinks in the advanced glycosylation endproducts by cleaving alpha-dicarbonyl-based protein crosslinks present in the advanced glycosylation endproducts. Certain agents useful are thiazolium salts. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated. A novel immunoassay for detection of the reversal of the nonenzymatic crosslinking is also disclosed.
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- Preventing and reversing advanced glycosylation endproducts
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The present invention relates to compositions and methods for inhibiting and reversing nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises a thiazolium compound capable of inhibiting, and to some extent reversing, the formation of advanced glycosylation endproducts of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated. A novel immunoassay for detection of the reversal of the nonenzymatic crosslinking is also disclosed.
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- Formamido and carboxyamido compounds which can be retained in brain
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According to the present invention, a novel compound group which can pass through blood-brain barrier (BBB) with carrying a drug thereon and stay within brain to release the drug and a well-known compound group having the properties described above are provided. The compound represented by the general formula STR1 wherein, R1 represents C1-6 alkyl which may be substituted by a group selected from hydroxyl, carboxyl, amino group which may be substituted by C1-6 alkyl, and a five- to seven-membered saturated heterocyclic ring, R2 represents hydrogen or C1-6 alkyl, R3 represents hydrogen or C1-6 alkyl which may be substituted by hydroxyl, R4 represents hydrogen or C1-6 alkyl, R5 represents an amino acid residue, or --S--R6 or --CO--R6 wherein R6 represents C1-14 alkyl which may be substituted by a five- to seven-membered saturated ring; C2-6 alkenyl; aryl; or a five- to seven-membered saturated ring; or the group represented by the general formula (IVa): STR2 wherein R1, R2, R3 and R4 have the same meanings as defined above, and ********* represents a single bond or a double bond provided that at least one of R1, R3 and R5 contains hydroxyl, carboxyl or amino, and a salt thereof.
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- Luminescence Characteristics of Thiamine Derivatives
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A detailed study of the fluorescence and phosphorescence characteristics of thiamine (Vitamin B1), thiamine pyrophosphate (cocarboxylase), and a number of related compounds has been undertaken.The attempt to enhance the phosphorescence of thiamine by several external heavy-atom species resulted in a new emission band, which has been assigned to a charge-transfer state.
- Gibson, Ernest P.,Turnbull, James H.
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p. 1288 - 1292
(2007/10/02)
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