Nitrosation of hydrochlorothiazide and the modes of binding of the N-nitroso derivative with two macrocycles possessing an 18-membered crown ether cavity

Simonov, Yurii A.; Fonarı, Marina S.; Duca, Gheorghe; Gonţa, Maria; Ganin, E. V.; Yavolovskii, A. A.; Gdaniec, Мaria; Lipkowski, Janusz

doi:10.1016/j.tet.2005.04.050

Cited by 12 publications

(8 citation statements)

References 17 publications

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“…Synthetic scheme for the preparation of nizatidine. 82,83 Journal of Medicinal Chemistry Product recalls provide negative consequences to the manufacturers; however, many reputed firms turn recall crises into opportunities. The increased awareness of patient safety has led to an implementation of preventive measures by many companies using an internal product recall team, implementing appropriate quality control procedures that are put in place to reduce the risk or perhaps even prevent the expenses associated with recalls.…”

Section: Discussionmentioning

confidence: 95%

“…In this case, the electrophilic substitution of nitrosyl cation (N + =O) occurs at aniline NH-that is relatively more powerful nucleophile in comparison to sulfamido groups (Figure 12). 82,83 The metabolic activation of N-nitroso-hydrochlorothiazide or NMPA is not expected to generate the highly carcinogenic diazoalkane metabolite; however, it is likely to produce the diazophenyl (Ph−N + N) metabolite. 84 Furthermore, a similar type of N-nitrosation is noted for niridazole and tolbutamide which are the nitrothiazole and sulfonamide classes of drugs, respectively.…”

Section: Drug Products Of Sartans In Combination Withmentioning

confidence: 99%

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Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

Bharate

2021

J. Med. Chem.

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A product recall is the outcome of a careful pharmacovigilance; and it is an integral part of drug regulation. Among various reasons for product recall, the detection of unacceptable levels of carcinogenic impurities is one of the most serious concerns. The genotoxic and carcinogenic potential of N-nitrosamines raises a serious safety concern, and in September 2020, the FDA issued guidance for the pharmaceutical industry regarding the control of nitrosamines in drug products. The FDA database shows that >1400 product lots have been recalled from the market due to the presence of carcinogenic N-nitrosamine impurities at levels beyond the acceptable intake limit of 26.5 ng/day. The drugs that were present in recalled products include valsartan, irbesartan, losartan, metformin, ranitidine, and nizatidine. This perspective provides a critical account of these product recalls with an emphasis on the source and mechanism for the formation of N-nitrosamines in these products.

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Section: Discussionmentioning

confidence: 95%

Section: Drug Products Of Sartans In Combination Withmentioning

confidence: 99%

Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

Bharate

2021

J. Med. Chem.

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“…DEN can be produced by the transformation of nitrite through many ways, 32,33 and DEN has been detected in foods frequently. [15][16][17] When humans are accustomed to eating pickles and bacon, their DEN exposure risk will increase drastically because such pickled foods often contain a high level of nitrites.…”

Section: Discussionmentioning

confidence: 99%

Mouse hepatic neoplasm formation induced by trace level and low frequency exposure to diethylnitrosamine through β-catenin signaling pathway

Leng

Chen

et al. 2015

Toxicology Research

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It has been reported that massive levels or/and high frequency exposure of diethylnitrosamine could induce hepatic neoplasm. However, it would be more interesting to figure out the hepatotoxic effects of diethylnitrosamine exposure at trace level and low frequency, which could be more common in our daily life. We found that both the mRNA and protein expression levels of β-catenin were aberrant in all liver tissues, accompanied by inflammation, steatosis, fibrosis and hepatic neoplasm after 10-week exposure of diethylnitrosamine (dissolved in sesame oil, 0.16 mmol per kg body weight) to mice. In addition, gradual increase in the mRNA expression of several pivotal risk factors (TNF-α, COX-2, PPAR-γ, AP-2, Smad-2, TGF-β1, and C-myc), as well as their protein expression levels, were associated with the aberrant expression or/and nucleus localization of β-catenin. Altogether, our results show that long-term diethylnitrosamine exposure at trace amounts and low frequency can also induce hepatotoxicity (including inflammation, steatosis and fibrosis) and consequently aberrant activation of β-catenin which in turn plays an important role in the initiation and promotion of liver tumors.

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“…N-Nitroso derivatives are known to possess carcinogenic properties (Lijinsky, 1992), and the route of inhibition of the nitrosation process is currently under discussion (Simonov et al, 2005).…”

Section: Commentmentioning

confidence: 99%

11-Nitroso-6,7,10,11,12,13,15,16-octahydro-9H-5,8,14,17-tetraoxa-11-azabenzocyclopentadecene

2005

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The title compound, C14H20N2O5, was prepared by the nitrosation of 6,7,10,11,12,13,15,16‐octahydro‐9H‐5,8,14,17‐tetraoxa‐11‐azabenzocyclopentadecene. The ligand has an intramolecular C—H⋯O hydrogen bond, resulting in the formation of a six‐membered ring. Apart from the near planar OC6H4O segment, the macrocycle contains gauche C—N and a mixture of gauche and anti C—O and C—C linkages. The nitroso group is not involved in any significant intermolecular interactions.

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Nitrosation of hydrochlorothiazide and the modes of binding of the N-nitroso derivative with two macrocycles possessing an 18-membered crown ether cavity

Cited by 12 publications

References 17 publications

Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

Mouse hepatic neoplasm formation induced by trace level and low frequency exposure to diethylnitrosamine through β-catenin signaling pathway

11-Nitroso-6,7,10,11,12,13,15,16-octahydro-9H-5,8,14,17-tetraoxa-11-azabenzocyclopentadecene

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