1947-00-8Relevant articles and documents
Targeting of phosphonoacetate to the liver: Synthesis of a phosphonoacetate-trilactoside conjugate
Bhat, Shridhar,Vaino, Andrew R.,Szarek, Walter A.
, p. 335 - 341 (2000)
As part of continuing studies on drug delivery to the human liver, a phosphonoacetate-trilactoside conjugate (12) has been synthesized in an overall yield of 23%. The shortness of the synthesis of this conjugate hinges upon a successful Michaelis-Arbuzov reaction of bromoacetamide 8 with tris-(trimethylsilyl) phosphite.
Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate
Tarozzi, Andrea,Marchetti, Chiara,Nicolini, Benedetta,D'Amico, Massimo,Ticchi, Nicole,Pruccoli, Letizia,Tumiatti, Vincenzo,Simoni, Elena,Lodola, Alessio,Mor, Marco,Milelli, Andrea,Minarini, Anna
, p. 283 - 291 (2016)
Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.
Structure-Activity Relationship of 18F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer
Dannoon, Shorouk,Ganguly, Tanushree,Cahaya, Hendry,Geruntho, Jonathan J.,Galliher, Matthew S.,Beyer, Sophia K.,Choy, Cindy J.,Hopkins, Mark R.,Regan, Melanie,Blecha, Joseph E.,Skultetyova, Lubica,Drake, Christopher R.,Jivan, Salma,Barinka, Cyril,Jones, Ella F.,Berkman, Clifford E.,Vanbrocklin, Henry F.
, p. 5684 - 5694 (2016)
A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [18F]4, [18F]5, and [18F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.
GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with “lock-in” function for central nervous system delivery
Zhao, Yi,Zhang, Li,Peng, Yao,Yue, Qiming,Hai, Li,Guo, Li,Wang, Qiantao,Wu, Yong
, p. 707 - 716 (2018)
Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT1) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT1, “lock-in” thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.
Supramolecular hydrogel formed by glucoheptonamide of l-lysine: simple preparation and excellent hydrogelation ability
Suzuki, Masahiro,Owa, Sanae,Shirai, Hirofusa,Hanabusa, Kenji
, p. 7302 - 7308 (2007)
We describe the simple preparation of new l-lysine derivatives with a gluconic or glucoheptonic group, their hydrogelation properties, and the thermal and mechanical properties of the supramolecular hydrogels. The l-lysine derivatives with a gluconic group have no hydrogelation ability, while the l-lysine-glucoheptonamide derivatives functioned as hydrogelators. Their hydrogelation abilities increased with the decreasing length of the spacer between the l-lysine segment and the glucoheptonic group. The compound, which has no spacer, formed a supramolecular hydrogel at 0.05 wt % in pure water. The thermal stability and high mechanical strength of the supramolecular hydrogels based on this compound significantly depended on the aqueous solutions. Electron microscopy and FTIR studies demonstrated?that the hydrogelators created a three-dimensional network through hydrogen bonding and hydrophobic interactions in the supramolecular hydrogel. In addition, it was found that hydrophobic interactions played an important role in the thermal stability of the supramolecular hydrogel.
MACROCYCLIC COMPOUNDS USEFUL AS CHITINASE INHIBITORS
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Paragraph 0126; 0136; 0138, (2021/07/29)
The present invention relates to macrocyclic compounds of formula (I) and their use as chitinase inhibitors as well as to pharmaceutical compositions and methods of preparation thereof. The compounds can in particular be used in the treatment, prevention and/or amelioration of asthma.
Method for synthesizing hexanediamine by taking caprolactam as raw material
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, (2019/11/21)
The invention discloses a method for synthesizing hexanediamine by taking caprolactam as a raw material. The method comprises the following steps that (1) after the hexanediamine, alkali and water aremixed, heating reflux is conducted, and thus 6-amino-caproate is obtained; (2) the 6-amino-hexanoate obtained in the step (1) is introduced into an amino protecting group to protect an amino end group, then acid is added for neutralization to generate aminocaproic acid with the amino protecting group; (3) after a product obtained in the step (2) is dried, a dehydration catalyst for amide is added, a heating reaction is conducted in the presence of an ammonia source to convert a carboxylic acid group into a cyano group, and thus product nitrile is obtained; and (4) after the product nitrile obtained in the step (3) is extracted and purified, catalytic hydrogenation is conducted to generate corresponding amine, then the protecting group is removed, and thus a target product can be obtained.
Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol
Maccari, Giorgio,Deodato, Davide,Fiorucci, Diego,Orofino, Francesco,Truglio, Giuseppina I.,Pasero, Carolina,Martini, Riccardo,De Luca, Filomena,Docquier, Jean-Denis,Botta, Maurizio
supporting information, p. 3332 - 3336 (2017/07/07)
In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.
CARBON MONOXIDE RELEASING NORBORNENONE COMPOUNDS
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Page/Page column 56; 140; 141, (2017/09/27)
The present invention provides organic compounds which are capable of releasing carbon monoxide under physiological conditions or pH trigger, and to the use of such compounds for conditioning a cell, tissue or organ, for example, to protect against ischaemic injury during a transplant event.
Novel glucose-based brain-targeting prodrug with locking function
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Paragraph 0012, (2016/10/10)
The invention discloses a novel glucose-based TDS modified brain-targeting prodrug with a locking function. The prodrug is of a structure shown in a general formula (I) (described in the specification) or pharmaceutically acceptable salt of hydrate of the structure, wherein X is -NH-(CH2)m-O-, -NH-(CH2)m-NH-, -C(O)-(CH2)m-NH-, -C(O)-(CH2)m-O-, -O-(CH2)m-O-, -O-(CH2)m-NH-; Y is -C(O)-(CH2)n-C(O)-; m represents 2-6, n represents 1-4; Drug is a drug acting on a central nervous system. A series of prodrugs provided by the invention, on the basis of glucose brain targeting, are added with a TDS part, so that the prodrugs have the locking function, brain targeting and center concentration of the drug can be improved, the curative effect of the drug is enhanced, and distribution of the drug in peripheral organs is reduced while toxic and side effects of the drug are reduced.
