- Bacterial Biosynthetic P450 Enzyme PikCD50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites
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Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enz
- Cheng, Fangyuan,Du, Lei,Durairaj, Pradeepraj,Guo, Jiawei,Li, Fengwei,Li, Shengying,Liu, Xiaohui,Long, Xiangtian,Ma, Li,Tang, Dandan,Zhang, Gang,Zhang, Wei,Zhang, Xingwang
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p. 14563 - 14571
(2021/11/12)
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- Synthesis and synergistic antimycobacterial screening of chlorpromazine and its metabolites
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The antimycobacterial activities of chlorpromazine and its metabolites were evaluated alone and in combination with antitubercular drugs. Although associated with limited antimycobacterial activity when tested individually, chlorpromazine and its metabolites exhibited clear synergy when tested in combination with a number of aminoglycosides as well as the active metabolite of rifampicin, 25-desaceteylrifampicin. The combination of chlorpromazine and spectinomycin was associated with the greatest synergy, yielding a fractional inhibitory concentration index (FICI) of 0.31. Synergistic interactions were also observed for combinations of 7-hydroxychlorpromazine or nor-chlorpromazine with kanamycin, streptomycin, spectinomycin and 25-desacetylrifampicin (FICI 0.19-0.5).
- Kigondu, Elizabeth M.,Njoroge, Mathew,Singh, Kawaljit,Njuguna, Nicholas,Warner, Digby F.,Chibale, Kelly
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supporting information
p. 502 - 506
(2014/04/17)
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- A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media
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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.
- Wisniewska, Joanna,Rzesnicki, Pawel,Topolski, Adrian
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scheme or table
p. 767 - 774
(2012/07/01)
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- Synthesis of potential drug metabolites by a modified Udenfriend reaction
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The scope and the limitations of a modified Udenfriend reaction for the one-step synthesis of potential drug metabolites were explored. Several drugs (clozapine, chlorpromazine, imipramine, buspirone, diltiazem, and propranolol) were subjected to modified Udenfriend conditions (Fe2+/Mn 2+/EDTA/ascorbic acid/O2). From each reaction, one to four oxidation products were obtained in 1-8% overall yield. Many of these products (9 out of 14) have been reported to be metabolites of the parent drugs in vivo. The products resulted mainly from aromatic hydroxylation, and are not readily accessible by conventional synthesis. Thus, the described reaction may be useful in drug discovery whenever a facile synthetic access is more important than high yields (e.g., for a fast derivatisation of compounds or the preparation of metabolites). Poorly water-soluble compounds cannot be converted, which is an important limitation of this method. 2010 American Chemical Society.
- Slavik, Roger,Peters, Jens-Uwe,Giger, Rudolf,Bürkler, Markus,Bald, Eric
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experimental part
p. 749 - 752
(2011/03/21)
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- The singlet oxygen oxidation of chlorpromazine and some phenothiazine derivatives. Products and reaction mechanisms
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(Chemical Equation Presented) A kinetic and product study of the reactions of chlorpromazine 1, N-methylphenothiazine 2, and N-ethylphenothiazine 3 with singlet oxygen was carried out in MeOH and MeCN. 1 undergoes exclusive side-chain cleavage, whereas the reactions of 2 and 3, in MeOH, afforded only the corresponding sulfoxides. A mechanism for the reaction of 1 is proposed where the first step involves an interaction between singlet oxygen and the side-chain dimethylamino nitrogen. This explains why no side-chain cleavage is observed for 2 and 3.
- Baciocchi, Enrico,Del Giacco, Tiziana,Lanzalunga, Osvaldo,Lapi, Andrea,Raponi, Daniele
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p. 5912 - 5915
(2008/02/10)
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