- Truly-Biocompatible Gold Catalysis Enables Vivo-Orthogonal Intra-CNS Release of Anxiolytics
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Being recognized as the best-tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly-catalytic Au-polymer composite by assembling ultrasmall Au-nanoparticles at the protein-repelling outer layer of a co-polymer scaffold via electrostatic loading. Illustrating the in vivo-compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled -for the first time- modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal.
- Adam, Catherine,Becker, Catherina G.,Hamilton, Lloyd,Ortega-Liebana, M. Carmen,Porter, Nicola J.,Sieger, Dirk,Unciti-Broceta, Asier,Valero, Teresa
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supporting information
(2021/11/22)
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- Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine
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The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.
- Bojarski, Andrzej J.,Bugno, Ryszard,Duszyńska, Beata,Hogendorf, Adam S.,Hogendorf, Agata,Kurczab, Rafa?,Lenda, Tomasz,Pietru?, Wojciech,Sata?a, Grzegorz,Staroń, Jakub,Wantuch, Anna,Warszycki, Dawid
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supporting information
(2021/06/02)
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- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
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Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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Page/Page column 37-39
(2020/12/14)
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- Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides
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A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.
- Johansen, Martin B.,Lindhardt, Anders T.
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p. 1417 - 1425
(2020/03/03)
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- Determination of fluoxetine hydrochloride via ion-pair complexation with alizarin red S
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Two UV-Vis spectrophotometric methods and one fluorimetric method have been developed for the quantitative determination of fluoxetine hydrochloride in bulk and pharmaceutical formulations. These methods are based on the ion-pair complex formation between alizarin red S and fluoxetine hydrochloride. In the first method (method A), the yellow-colored complex obtained in acidic medium was extracted with chloroform and the absorbance of the chloroformic solution was measured at 425 nm. Beerís law limits (9.5 ? 48 μg/mL), the molar absorptivity (5256 L ∑ mol-1 ∑ cm-1), and the complex composition (1: 1) were determined. In the second method (method B), the yellow complex fluoxetine ? alizarin red S extracted in chloroform was broken in alkaline medium, and the absorbance of the resulting violet-colored free dye was measured at 524 nm. A linear relationship was observed in the range of 9.0 ? 54 μg/mL. In the third method (method C) the fluorescence intensity of the fluoxetine ? alizarin red S complex, obtained in the same manner as for method A, was measured at 594 nm after excitation at 425 nm. The fluorescence intensity was proportional to the drug concentration in the linear range of 2.7-10.2 μg/mL. The limits of detection and quantification have also been calculated. Furthermore, the proposed methods have been successfully applied for the assay of the drug in pharmaceutical dosage forms.
- Constantinescu, Ioana Clementina,Neagu, Alexandra Filareta,Uivarosi, Valentina
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p. 1293 - 1303
(2019/01/04)
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- Fe(OTf)3-catalyzed tandem Meyer-Schuster rearrangement/intermolecular hydroamination of 3-aryl propargyl alcohols for the synthesis of acyclic β-Aminoketones
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Fe(OTf)3-catalyzed synthesis of acyclic β-aminoketones from 3-aryl propargyl alcohols and nitrogen nucleophiles were investigated. Results showed that propargyl alcohols without bulky groups α to the hydroxyl group underwent the transformation smoothly. Sulphonamides exhibited the higher reactivity than amides as the nitrogen nucleophiles and the transformation of acyclic β-aminoketones were finished in shorter reaction time and higher yields. Finally, racemic fluoxetine was efficiently accessed with the present reaction as the first step. This novel synthesis of acyclic β-aminoketones probable proceeded a Fe(OTf)3-catalyzed Meyer-Schuster rearrangement of 3-aryl propargyl alcohols, followed by a intermolecular hydroamination between nitrogen nucleophiles and α, β-unsaturated ketones.
- Tao, Ruiheng,Yin, Yan,Duan, Yongbin,Sun, Yuxing,Sun, Yue,Cheng, Fengkai,Pan, Jinpeng,Lu, Cheng,Wang, Yuan
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p. 1762 - 1768
(2017/03/08)
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- A model target anti-tumor medicament and its preparation method and application (by machine translation)
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This invention relates to the targeting of antineoplastic eEF2K of a small molecule inhibitor, its formula (I), formula (II) the structure of the formula (III): Formula (I), formula (II) compound of the formula (III) structure and its pharmaceutically acceptable salt thereof can kill cancer cells, the healthy organism cells are not affected, to various tumor is markedly inhibited, in particular breast cancer, glioma, stomach cancer, liver cancer cells is markedly inhibited. (by machine translation)
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- From precursor to catalyst: The involvement of [Ru(η5-Cp?)Cl2]2 in highly branch selective allylic etherification of cinnamyl chlorides
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(RuCp?Cl2)2, a general entry into Cp?Ru sandwich and half-sandwich chemistry was first used as a precatalyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preliminary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as well.
- Siddappa, Ravi Kumara Guralamatta,Chang, Chih-Wei,Chein, Rong-Jie
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p. 1031 - 1035
(2015/02/19)
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- Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
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We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee). This journal is the Partner Organisations 2014.
- Calow, Adam D. J.,Fernandez, Elena,Whiting, Andrew
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p. 6121 - 6127
(2014/08/05)
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- Molecular basis for selective serotonin reuptake inhibition by the antidepressant agent fluoxetine (Prozac)
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Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model comparedwith the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity. Copyright
- Andersen, Jacob,Stuhr-Hansen, Nicolai,Zachariassen, Linda Gronborg,Koldso, Heidi,Schiott, Birgit,Stromgaard, Kristian,Kristensen, Anders S.
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p. 703 - 714
(2014/04/17)
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- Room temperature, metal-free arylation of aliphatic alcohols
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Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron
- Ghosh, Raju,Lindstedt, Erik,Jalalian, Nazli,Olofsson, Berit
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- From precursor to catalyst: The involvement of [Ru(η5- Cp*)Cl2]2 in highly branch selective allylic etherification of cinnamyl chlorides
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(RuCp*Cl2)2, a general entry into Cp*Ru sandwich and half-sandwich chemistry was first used as a precatalyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preliminary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as well.
- Siddappa, Ravi Kumara Guralamatta,Chang, Chih-Wei,Chein, Rong-Jie
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supporting information
p. 1031 - 1035
(2014/02/14)
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- NO-SSRIs: Nitric oxide chimera drugs incorporating a selective serotonin reuptake inhibitor
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Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 h. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter; however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061) were made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide cotherapy of neuropathologies concomitant with depression.
- Abdul-Hay, Samer,Schiefer, Isaac T.,Chandrasena, R. Esala P.,Li, Min,Abdelhamid, Ramy,Wang, Yue-Ting,Tavassoli, Ehsan,Michalsen, Bradley,Asghodom, Rezene T.,Luo, Jia,Thatcher, Gregory R. J.
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p. 656 - 661
(2011/11/07)
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- Preparation of fluoxetine by multiple flow processing steps
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Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
- Ahmed-Omer, Batoul,Sanderson, Adam J.
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p. 3854 - 3862
(2011/06/23)
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- METHOD FOR THE PREPARATION OF N-METHYL-ARYLOXY-PROPANAMINE DERIVATIVES
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The present invention is related to a method for the preparation of N-methyl-aryloxy-propanamine derivatives, which comprises reacting a suitable uretane derivative of the Formula (XXIV) with a Grignard reagent.
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Page/Page column 35-36
(2010/04/03)
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- Novel synthetic route to fluoxetine
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Racemic fluoxetine was synthesized from 3-benzoylpropionic acid in five steps in 54% overall yield. Copyright
- Schulze, Matthias
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experimental part
p. 3415 - 3422
(2011/01/12)
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- Chimeric Nitrate Esters and Use of the Same in a Treatment for Depression
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Chimeric nitrate esters and their use in the treatment of depression are disclosed. The chimeric nitrate esters also are useful in the treatment of depression and comorbidity associated with aging.
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Page/Page column 20
(2009/07/25)
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- Substituted propanolamines and alkylamines derived from fluoxetine as potent appetite suppressants
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A series of propanolamine and alkylamine analogues of fluoxetine (7-26, 28-31) were synthesized and assessed for their anorexigenic and antidepressant activities. Effect of various substituents at C-4 aryl position of fluoxetine has also been studied. Most of the propanolamine analogues (7-13, 16-26) displayed significant anorexigenic activity but interestingly they were devoid of antidepressant activity whereas anorexigenic as well as antidepressant activity was retained in the alkylamine series (28-31). Compounds 10 and 26 emerged as the most active compound and anorexigenic activity was better (83.67% and 82.45%) compared to fluoxetine (81.25%).
- Bhandari, Kalpana,Srivastava, Shipra,Shanker, Girija,Nath, Chandishwar
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p. 1739 - 1747
(2007/10/03)
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- Anti-proliferative drugs
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The present invention relates to methods for the treatment of diseases associated with hyper-proliferation of cells by administering to a subject in need a therapeutically effective amount of at least one psychotropic agent. Specific proliferative diseases against which psychotropic agents were found to be effective are cancer, including multi-drug resistant cancer and diseases associated with hyper-proliferation of the skin cells, such as psoriasis and hyperkeratosis.
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- Methods and compounds for treating depression and other disorders
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The present invention features compounds active at both the serotonin reuptake site and the N-methyl-D-aspartate (NMDA) receptor and the use of such compounds for treating different disorders. Compounds having activity at the serotonin reuptake site and the NMDA receptor (“multi-active compounds”) can be used to treat different types of disorders such as depression, obsessive-compulsive disorders (OCD), sleep, disorders, sexual dysfunction, and eating disorders. Preferably, the multi-active compounds are used to treat depression.
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- Pulmonary delivery for bioconjugation
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Methods of and compositions for pulmonary delivery of therapeutic agents which are capable of forming covalent bonds with a site of interest or which have formed a covalent bond with a pulmonary solution protein are disclosed. Therapeutic agents useful in the invention include wound healing agents, antibiotics, anti-inflammatories, anti-oxidants, anti-proliferatives, immunosupressants, anti-infective and anti-cancer agents.
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- Synthesis, anorexigenic activity and QSAR of substituted aryloxypropanolamines
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Substituted aryloxypropanolamines (6-20) were synthesized and evaluated for their anorexigenic activity. Among them 4-cyanoaryloxy (7), 2-methylaryloxy (9), 2-methoxyl aryloxy (10), 4-acetamidoaryloxy (15), 4-bromoaryloxy (16) and 4-ethylaminoaryloxy (20) exhibited potent anorexigenic activity. According to QSAR studies, the electronic parameter 'σ' plays an important role in describing the variance in activity. Birkhaeuser Boston 2004.
- Srivastava, Shipra,Bhandari, Kalpana,Shankar, Girija,Singh,Saxena, Anil K.
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p. 631 - 642
(2007/10/03)
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- Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor
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The present invention concerns a method of synthesizing fluoxetine hydrochloride. The method includes the synthesis of 3-methylamino-1-phenyl-1-propanol by reduction of 1-phenyl-3-methylamino-1-propen-1-one with sodium borohydride and acetic acid.
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- Method and pharmaceutical composition for the treatment of cancer
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A method of chemosensitization which comprises administering at least one chemotherapeutic agent and at least one 3-aryloxy-3-phenylpropylamine to a subject in need thereof.
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- Pure S(+)isomer fluoxetine
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Methods and compositions are disclosed utilizing the pure S(+) isomer of fluoxetine which is a potent antidepressant and appetite suppressant substantially free of unwanted, adverse toxic or psychological effects, for the treatment of human depression. In addition, methods and compositions are disclosed utilizing the pure S(+) isomer of fluoxetine which is useful in treating migraine headaches, pain, in particular chronic pain, and obsessive-compulsive disorders. Further, methods and compositions for treating a condition alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets in a human using optically pure S(+) fluoxetine are disclosed.
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- Fluoxetine process from benzoylacetonitrile
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A synthesis of fluoxetine is disclosed. The process begins with benzoylacetonitrile, which is reduced, optionally in the presence of a chiral ligand, to produce the corresponding aminoalcohol, and the amine is carbamoylated without isolation. The alcohol is deprotonated and reacted with 4-chloro- or 4-fluoro benzotrifluoride or with 4-trifluoromethylphenol to provide a carbamate of fluoxetine. The carbamate is reduced with a hydride or with borane to provide fluoxetine free base. The process may be employed for the synthesis of individual enantiomers of fluoxetine.
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- Fluoxetine process from benzoylpropionic acid
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A synthesis of fluoxetine is disclosed. The process begins with a lower alkyl ester of 3-benzoylpropionic acid, which is reduced in the presence of a chiral ligand to produce the corresponding γ-hydroxy ester, and the ester is cleaved. The free acid is then condensed with the alcohol to form a γ-lactone, which is treated with ammonia to provide the γ-hydroxy amide. The amide undergoes a Hoffman rearrangement to provide a 2-oxo-1,3 oxazine, which is reduced to 3-(methylamino)-1-phenyl-1-propanol. The alcohol is deprotonated and reacted with a 4-chloro- or 4-fluoro benzotrifluoride to provide fluoxetine free base.
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- Preparation and uses of hydrocarbylnitrones
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Nitrones are produced by reaction of primary amine with aldehyde or ketone, in the presence of a transition metal-containing oxidation catalyst, and a peroxidic compound. The nitrone can then be reacted with a vinylaromatic compound to produce a 2-hydrocarbyl-5-arylisoxazolidine. Both such reactions can be conducted concurrently by including the vinylaromatic compound in the initial reaction mixture. Hydrogenation of the 2-hydrocarbyl-5-arylisoxazolidine, e.g., using hydrogen and a palladium-carbon catalyst, forms an N-hydrocarbyl-3-aryl-3-hydroxypropylamine. Such reactions enable, inter alia, synthesis of the racemic hydrochloride salt of N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]-propylamine, known generically as fluoxetine hydrochloride, a widely used antidepressant.
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- Preparation and uses of N-methylnitrone
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Oxidation of secondary amines with hydrogen peroxide and sodium tungstate is reported to give good yields of nitrones. However, when using dimethylamine in this manner, a considerable amount of N,N-dimethylformamide was produced as a co-product. To more selectively produce N-methylnitrone from dimethylamine, a two-step process is used which comprises (a) mixing together dimethylamine and a peroxidic compound, and subjecting the resultant mixture to reaction conditions effective to form a reaction mixture in which N,N-dimethylhydroxylamine has been formed; and (b) mixing together (i) reaction mixture from (a), (ii) a peroxidic compound, and (iii) a transition metal-containing oxidation catalyst, and subjecting the resultant mixture to reaction conditions effective to form a reaction mixture in which N-methylnitrone has been formed. Highest yields of N-methylnitrone are achieved by conducting step (b) at a pH in the range of 7 to about 12, and at a temperature in the range of about -10° to about 100° C.
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- Process for the preparation of fluoxetine
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An improved process for the preparation of fluoxetine. The invention is concerned with an improved process for the preparation of the antidepressant, fluoxetine hydrochloride, or N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride, by simultaneous debenzylation and catalytic hydrogenation of 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base with the aid of Pd/C, Pt/C or Pd-Pt/C at a hydrogen pressure of 5 bar at 50° C. with ethyl acetate as a solvent to obtain 1-phenyl-3-(N-methylamino)-propan-1-ol. This compound is then selectively etherified with 1-chloro-4-trifluoromethylbenzene in N-methylpyrrolidone at 80° C. in the presence of potassium t-butoxide to form N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, or fluoxetine base, which is transformed in a known manner to fluoxetine hydrochloride, or N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride. The yield of fluoxetine hydrochloride is 85-87% of the theoretical.
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- Treatment of obesity with aryloxyphenylpropylamines
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3-Aryloxy-3-phenylpropylamines and acid addition salts thereof are useful in blocking uptake of monoamines by brain neurons, and are thus effective in treating disorders of sleep, sexual performance, appetite, muscular function, and pituitary function.
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- Aryloxyphenylpropylamines in treating depression
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3-Aryloxy-3-phenylpropylamines and acid additions salts thereof, useful as psychotropic agents, particularly as anti-depressants.
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