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Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Jan Kiebist, Martin Hofrichter, Ralf Zuhse, Katrin Scheibner
Moreover, during the enzymatic synthesis of 74, two by-products were identified: the N-formyl derivatives (75 and 76) of volixibat (72) and N-demethyl volixibat (73) (Fig. 18.21). Both could be further hydrolyzed to give the envisaged metabolites 73 and 74. The formation of these N-formyl derivatives might be the result of a second hydroxylation of the same methyl group and subsequent water release from the resulting geminal alcohol (gem-diol) as it has been demonstrated for the oxidation of alcohols into aldehydes by UPOs (Hofrichter and Ullrich, 2014). Proposed mechanism of UPO-catalyzed N-demethylation of volixibat (72). The reaction may proceed via unstable hemiaminal intermediates and formation of N-formyl derivatives (75 and 76) emerging from gem-diol intermediates.
History of antifungals
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Emily L. Larkin, Ali Abdul Lattif Ali, Kim Swindell
The advent of echinocandins (Figure 1.1), was heralded by the development and approval of caspofungin acetate (Cancidas; Merck & Co., Inc.) for the treatment of candidiasis in 2002 [66]. The echinocandins are a group of large, semisynthetic, cyclic lipopeptides discovered in the 1970s. Large molecular weight may explain their poor absorption through the digestive tract. Therefore, all three commercially available echinocandin compounds—caspofungin acetate, micafungin, and anidulafungin—are used only intravenously [74,75]. Echinocandins inhibit synthesis of 1,3-ß-D-glucan, an essential component of the fungal cell wall [76]. The synthesis of caspofungin acetate based on pneumocandin B0 requires chemical modification at two sites of the peptide core, reduction of a primary amide to an amine, and condensation of the hemiaminal moiety with ethylenediamine [76].
Compatibility investigation for a new antituberculotic fixed dose combination with an adequate drug delivery
Published in Drug Development and Industrial Pharmacy, 2020
Valentina Petruševska, Kornelija Lasić, Ana Mornar
For the second peak with the RRT = 1.04 and molecular ion with m/z 966.4991 [M + H]+, collision energies from 10 eV to 45 eV were used. Formation of the major fragment ion at m/z 934.4719 was observed, corresponding to loss of CH3OH. Additional loss of water molecule followed by the loss of CH2CO resulted in formation of fragment ions with m/z 916.4596 and 874.4493, respectively (Figure 6(b)). m/z value for the molecular ion of the peak at RRT = 1.04 was 119 higher than the m/z of rifabutin molecular ion. It led to the assumption of intramolecular condensation due to the addition primary amine group of isoniazid to the carbonyl group of rifabutin, forming thereby hemiaminal with the elimination of water [29]. Such product has a somewhat higher log Pvalue (3.7) than what is calculated with Marvin chemical editor (Chemaxon, Budapest, Hungary) for rifabutin (3.1) under the conditions of testing. Therefore, it is slightly less polar than the related active substance which could explain its elution with the RRT = 1.04.
N-terminal α-amino group modification of antibodies using a site-selective click chemistry method
Published in mAbs, 2018
De-zhi Li, Bing-nan Han, Rui Wei, Gui-yang Yao, Zhizhen Chen, Jie Liu, Terence C.W. Poon, Wu Su, Zhongyu Zhu, Dimiter S. Dimitrov, Qi Zhao
We synthesized a new 2-PCA derivative, 6-AM-2-PCA, that retains the capacity of 2-PCAs to react with N-terminal amino acids of proteins and form stable covalent bonds. In addition, 6-AM-2-PCA is capable of reacting with DBCO derivatives. Site-selectivity of 6-AM-2-PCA for N-terminal α-amines was confirmed by MS analysis. Modification efficiency can be determined by concentrations of free 6-AM-2-PCA. Further experiments demonstrated that 6-AM-2-PCA is able to modify proteins in a single step under physiological conditions that are moderate enough to permit biomolecular activities. MacDonald et al demonstrated that 2-PCA afforded 43% to 95% modification for different proteins.28 Notably, 33% of uteroglobin, a covalent homodimer, was singly modified at either of two N termini. Our studies demonstrated that 6-AM-2-PCA as a derivative of 2-PCA afforded >79% modification of anti-HER2 Fab with single and double labels. Similar to uteroglobin, we did not obtain the complete formation of double labels per anti-HER2 Fab even at 100-fold excess of reagents. Interestingly, half of bis-modified proteins formed hemiaminal products after the aldehyde-amine reaction. Our further study revealed that 6-AM-2-PCA mainly reacted to the N-terminus of anti-HER2 Fab heavy chain. Steric hindrance from the tertiary structure of the N-terminal region may affect selectivity to either heavy or light chains of the antibody. The 2-PCA method is specific for the native N termini of some antibodies.28 Therefore, it will be interesting to investigate reaction conditions of 6-AM-2-PCA for different antibodies in future studies.
The metabolism of the dual orexin receptor antagonist daridorexant
Published in Xenobiotica, 2023
Alexander Treiber, Stephane Delahaye, Aude Weigel, Päivi Aeänismaa, John Gatfield, Swen Seeland
The metabolism of daridorexant in liver microsomes was characterised by four pathways including aliphatic hydroxylation to the benzylic alcohol M3, O-demethylation to M4, hydroxylation in the anisolyl moiety to M11, and initial hydroxylation of the 5-position of the pyrrolidine ring. The latter hemiaminal hydrolysed to a ring-open amino aldehyde and then recyclized with the benzimidazole moiety to the final piperidinol metabolite M5 (Treiber et al. 2023). Human liver microsomes yielded M3–M5 which were also present in microsomal experiments in the rat and mouse. M11 appeared to be a rat-specific pathway based on in vitro data but was also observed – as its glucuronide conjugate M6 – in mouse bile. M3–M5 were also present with human hepatocytes but accompanied by a number of downstream products. The alcohol M3 was further oxidised to the corresponding aldehyde M1 and the acid M2, likely by non-P450 reactions. M7 and M10 were oxidative cross-products of the three primary pathways, while M9 was the glucuronide conjugate of M4. M8 was the product of a fourth pathway resulting from combined hydroxylation in the anisolyl triazole moiety and subsequent glucuronidation. Its primary metabolite is unknown. M8 was different from M6, and M11 was excluded as its precursor based on hydrolysis experiments with glucuronidase (data not shown). The pattern in rat and mouse hepatocytes qualitatively resembled those in man, but showed quantitative differences. M6 and M9 were the main products in the rat while M9 was by far the most prominent entity in the mouse. M8 was present in small amounts in both species. From a metabolism perspective, both rodent species therefore qualified well for use in preclinical safety testing.