60-87-7Relevant academic research and scientific papers
Side-Chain Effects on Phenothiazine Cation Radical Reactions
Sackett, Patricia Holt,Mayausky, J. S.,Smith, Theresa,Kalus, Susan,McCreery, Richard L.
, p. 1342 - 1347 (1981)
The cation radical of each of the phenothiazine tranquilizers is a likely intermediate in the metabolism of the drugs to at least two of the three major metabolic classes, the sulfoxides and the hydroxylated derivatives.Previous work has shown that the reactions of the radical are highly dependent on the environment, patricularly the presence of nucleophiles.The present report discusses the effect of cation radical structure on the formation of sulfoxide and hydroxylated metabolites in vitro.Cyclic voltammetry, spectrophotometry, and liquid chromatography were used to examine reactions of various phenothiazine radicals in aqueous buffers.A radical with a three-carbon aliphatic side chain (e.g., chlorpromazine) forms solely sulfoxide and parent unless amine nucleophiles are present, in which case hydroxylation occurs.A shorter side chain (e.g., promethazine) causes radical dimerization and pronounced hydroxylation, regardless of external nucleophiles.A piperazine side chain (e.g., fluphenazine) promotes hydroxylation, with some sulfoxide observed.The results indicate that a deprotonated amine is necessary for hydroxylation and that the amine may be present in the original drug rather than an external nucleophile.In addition to information about cation radical reactions, the redox properties of several different phenothiazines are presented.
Design, synthesis, and validation of a novel [11c]promethazine pet probe for imaging abeta using autoradiography
Behof, William J.,Boules, Mariam I.,Haynes, Justin R.,Koktysh, Dmitry,Pham, Wellington,Rosenberg, Adam J.,Tantawy, Mohammed N.,Whitmore, Clayton A.
, (2021/05/28)
Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer’s disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.
AMYLOID-BINDING COMPOUNDS AND METHODS OF USE THEREOF
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Paragraph 0078-0079, (2021/01/25)
A method of screening for amyloid-binding compounds, amyloid-binding compounds, and a method of detecting amyloid-β (Abeta) plaques in a subject are disclosed. The method of screening for amyloid-binding compounds includes combining amyloid, a dye, and at least one test compound to form a sample solution; equilibrating the sample solution; measuring a fluorescence signal of the sample solution; and comparing the measured fluorescence signal of the sample to a control; wherein attenuation of the fluorescence signal, as compared to the control, indicates that one or more of the test compounds bind amyloid. The amyloid-binding compound includes a compound detected by the screening method. The method of detecting amyloid-β (Abeta) plaques in a subject includes administering one or more of the amyloid-binding compounds to the subject, and detecting the compound within the subject.
Cobalt-Catalyzed Markovnikov Selective Sequential Hydrogenation/Hydrohydrazidation of Aliphatic Terminal Alkynes
Chen, Jieping,Shen, Xuzhong,Lu, Zhan
supporting information, p. 14455 - 14460 (2020/10/13)
Here, we reported for the first time a mechanistically distinctive cobalt-catalyzed Markovnikov-type sequential semihydrogenation/hydrohydrazidation of aliphatic terminal alkynes in one pot. A cobalt hydride species was employed as two roles for both a unique metal-catalyzed Markovnikov-type insertion of the aliphatic terminal alkynes and then metal-catalyzed hydrogen atom transfer of alkenes. This operationally simple protocol exhibits excellent functional group tolerance and step economy. The hydrazone products could be easily transferred to various valuable amine derivatives.
Coupling body-benzonorbornene oligomer- (by machine translation)
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Paragraph 0189, (2016/10/07)
The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.
A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media
Wisniewska, Joanna,Rzesnicki, Pawel,Topolski, Adrian
scheme or table, p. 767 - 774 (2012/07/01)
The oxidative degradation of phenothiazine derivatives (PTZ) by manganese(III) was studied in the presence of a large excess of manganese(III)-pyrophosphate (P2O7 2-), phosphate (PO4 3-), and H+ ions using UV-vis. spectroscopy. The first irreversible step is a fast reaction between phenothiazine and manganese pyrophosphate leading to the complete conversion to a stable phenothiazine radical. In the second step, the cation radical is oxidized by manganese to a dication, which subsequently hydrolyzes to phenothiazine 5-oxide. The reaction rate is controlled by the coordination and stability of manganese(III) ion influenced by the reduction potential of these ions and their strong ability to oxidize many reducing agents. The cation radical might also be transformed to the final product in another competing reaction. The final product, phenothiazine 5-oxide, is also formed via a disproportionation reaction. The kinetics of the second step of the oxidative degradation could be studied in acidic phosphate media due to the large difference in the rates of the first and further processes. Linear dependences of the pseudo-first-order rate constants (k obs) on [Mn III] with a significant non-zero intercept were established for the degradation of phenothiazine radicals. The rate is dependent on [H+] and independent of [PTZ] within the excess concentration range of the manganese(III) complexes used in the isolation method. The kinetics of the disproportionation of the phenothiazine radical have been studied independently from the further oxidative degradation process in acidic sulphate media. The rate is inversely dependent on [PTZ+.], dependent on [H+], and increases slightly with decreasing H+ concentration. Mechanistic consequences of all these results are discussed.
Compositions for Nasal Administration of Phenothiazines
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, (2010/09/05)
Provided herein are pharmaceutical compositions comprising phenothiazines or derivatives thereof that are formulated for nasal administration. Also provided herein are methods of utilizing the same.
CONTROLLED RELEASE COMPOSITIONS AND METHODS FOR USING SAME
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Page 27, (2010/02/06)
Pharmaceutical preparations adapted for mucosal delivery, preferably for nasal delivery, which can be easily and safely used over days to weeks with minimal side effects. The pharmaceutical preparations comprise microcapsules comprising at least one pharmaceutically active agent. The microcapsules provide controlled release of the pharmaceutically active agent. Cytotoxicity is avoided for cytotoxic pharmaceutically active agents and/or for cytotoxic dosages by one or more of the following: (a) manipulating the mucosal transport rate of the pharmaceutically active agent through the mucosal bodies to achieve a transport rate which is substantially the same as the controlled release rate, and/or (b) selecting only a most active and/or less cytotoxic enantiomer of the pharmaceutically active agent for use in the pharmaceutical preparation.
Reduction potentials of flavonoid and model phenoxyl radicals. Which ring in flavonoids is responsible for antioxidant activity?
Jovanovic, Slobodan V.,Steenken, Steen,Hara, Yukihiko,Simic, Michael G.
, p. 2497 - 2504 (2007/10/03)
Model phenoxyl and more complex flavonoid radicals were generated by azide radical induced one-electron oxidation in aqueous solutions. Spectral, acid-base and redox properties of the radicals were investigated by the pulse radiolysis technique. The physicochemical characteristics of the flavonoid radicals closely match those of the ring with the lower reduction potential. In flavonoids which have a 3,5-dihydroxyanisole (catechins), or a 2,4-dihydroxyacetophenone (hesperidin, rutin, quercetin)-like A ring and a catechol- or 2-methoxyphenol-like B ring, the antioxidant active moiety is clearly the B ring [reduction potential difference between the model phenoxyls is ΔE(A-B ring models) > 0.1 V]. In galangin, where the B ring is unsubstituted phenyl, the antioxidant active moiety is the A ring. Even though the A ring is not a good electron donor, E7, > 0.8/NHE V, it can still scavenge alkyl peroxyl radicals, E7, = 1.06 V, and the Superoxide radical, E7 > 1.06 V. Quercetin is the best electron donor of all investigated flavonoids (measured E10.8 = 0.09 V, and calculated E7 = 0.33 V). The favourable electron-donating properties originate from the electron donating O-3 hydroxy group in the C ring, which is conjugated to the catechol (B ring) radical through the 2,3-double bond. The conjugation of the A and B rings is apparently minimal, amounting to less than 2.5% of the substituent effect in either direction. Thus, neglecting the acid-base equilibria of the A ring, and using those of the B ring and the measured values of the reduction potentials at pH 3,7 and 13.5, the pH dependence of the reduction potentials of the flavonoid radicals can be calculated. In neutral and slightly alkaline media (pH 7-9), all investigated flavonoids are inferior electron donors to ascorbate. Quercetin, E7 = 0.33 V, and gallocatechins, E7 = 0.43 V, can reduce vitamin E radicals (assuming the same reduction potential as Trolox C radicals, E7 = 0.48 V). Since all investigated flavonoid radicals have reduction potentials lower than E7 = 1.06 V of alkyl peroxyl radicals, the parent flavonoids qualify as chain-breaking antioxidants in any oxidation process mediated by these radicals.
Phenothiazinealkaneamines for treatment of neurotoxic injury
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, (2008/06/13)
Compounds, compositions and methods of treatment are described to control brain damage associated with anoxia or ischemia which typically follows such conditions as stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of a phenothiazinealkaneamine compound as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of the formula STR1 wherein each of R1 and R2 is hydrido; wherein each of R3 and R4 is independently selected from hydrido, methyl and ethyl; wherein each of R5 and R6 is independently selected from methyl, ethyl and n-propyl; wherein X is sulfur; wherein m is zero; and wherein n is two.
