Elucidation of Chalkophomycin Biosynthesis Reveals N-Hydroxypyrrole-Forming Enzymes DOI Creative Commons
Anne Marie Crooke, Anika K. Chand, Zheng Cui

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(23), P. 16268 - 16280

Published: May 29, 2024

Reactive functional groups, such as N-nitrosamines, impart unique bioactivities to the natural products in which they are found. Recent work has illuminated enzymatic N-nitrosation reactions microbial product biosynthesis, motivating interest discovering additional metabolites constructed using reactivity. Here, we use a genome mining approach identify over 400 cryptic biosynthetic gene clusters (BGCs) encoding homologues of N-nitrosating enzyme SznF, including BGC for chalkophomycin, CuII-binding metabolite that contains C-type diazeniumdiolate and N-hydroxypyrrole. Characterizing chalkophomycin enzymes reveals previously unknown responsible N-hydroxypyrrole first prolyl-N-hydroxylase, key step assembly diazeniumdiolate-containing amino acid graminine. Discovery this pathway enriches our understanding logic employed constructing unusual heteroatom–heteroatom bond-containing enabling future efforts discovery biocatalysis.

Language: Английский

Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed DOI Open Access
Yupeng Li, Stephen S. Hecht

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4559 - 4559

Published: April 20, 2022

Carcinogenic N-nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens-widely detectable relatively low levels food, water, cosmetics, drugs-are well-established powerful animal carcinogens. The electrophiles resulting from cytochrome P450-mediated metabolism N-nitrosamines can readily react with DNA form covalent addition products (DNA adducts) that play a central role carcinogenesis if not repaired. In this review, we aim to provide comprehensive updated review progress on metabolic activation interactions 10 carcinogenic which humans are commonly exposed. Certain adducts such as O6-methylguanine established miscoding properties roles cancer induction process, whereas others have been linked high incidence types cancers. We hope data summarized here will help researchers gain better understanding bioactivation these facilitate further research their toxicologic properties.

Language: Английский

Citations

111
Risk assessment of N‐nitrosamines in food DOI Creative Commons

Dieter Schrenk,

Margherita Bignami,

Laurent Bodin

et al.

EFSA Journal, Journal Year: 2023, Volume and Issue: 21(3)

Published: March 1, 2023

EFSA was asked for a scientific opinion on the risks to public health related presence of

Language: Английский

Citations

73
What is the role of nitrate/nitrite in trace organic contaminants degradation and transformation during UV-based advanced oxidation processes? DOI
Xiuwei Ao, Xi Zhang, Wenjun Sun

et al.

Water Research, Journal Year: 2024, Volume and Issue: 253, P. 121259 - 121259

Published: Feb. 5, 2024

Language: Английский

Citations

19
Multicomponent reactions (MCRs) yielding medicinally relevant rings: a recent update and chemical space analysis of the scaffolds DOI Creative Commons

Mukesh Tandi,

Vaibhav Sharma, B. Gopal

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(2), P. 1447 - 1489

Published: Jan. 1, 2025

We have reviewed the recently reported multicomponent reactions (MCRs) yielding cyclic frameworks in a single pot from simple building blocks under mild conditions. These MCRs may prove to be useful for drug discovery projects.

Language: Английский

Citations

3
Developing structure-activity relationships for N-nitrosamine activity DOI Creative Commons
Kevin P. Cross, David J. Ponting

Computational Toxicology, Journal Year: 2021, Volume and Issue: 20, P. 100186 - 100186

Published: Sept. 8, 2021

The detection of N-nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that N-nitrosamine risk assessments be performed on all medical products [EMA/351053/2019 rev 1 (2019)]. Regulation impurity levels pharmaceutical drug substances and is described the ICH M7(R1) guideline where they are referred as "cohort-of-concern" compounds potent rodent carcinogens [Kroes et. al. 2004]. EMA, U.S. FDA other have set provisional acceptable daily intake limits for N-nitrosamines calculated from carcinogenicity TD50 values experimentally measured or close analogs. class-specific limit can adjusted based upon a structure activity relationship analysis (SAR) comparison with analogs having established data [EMA/369136/2020, (2020)]. To investigate whether improvements SARs more accurately predict carcinogenic potency, an ad hoc workgroup 23 companies universities was goals addressing scientific issues including: reporting review mutagenicity reaction mechanisms, collection available, public relevant experimental data, development structure–activity relationships consistent mechanisms prediction potency categories, improved methods calculating mechanistic Here we describe this collaboration our progress date towards mechanistically relationships. We propose improving assessment by first establishing dominant mechanism prior retrieving appropriate use read-across exercises.

Language: Английский

Citations

73
What Makes a Potent Nitrosamine? Statistical Validation of Expert-Derived Structure–Activity Relationships DOI Creative Commons
Robert Thomas, Rachael E. Tennant,

Antonio Anax Falcão de Oliveira

et al.

Chemical Research in Toxicology, Journal Year: 2022, Volume and Issue: 35(11), P. 1997 - 2013

Published: Oct. 27, 2022

The discovery of carcinogenic nitrosamine impurities above the safe limits in pharmaceuticals has led to an urgent need develop methods for extending structure–activity relationship (SAR) analyses from relatively limited datasets, while level confidence required that SAR indicates there is significant value investigating effect individual substructural features a statistically robust manner. This challenging exercise perform on small dataset, since practice, compounds contain mixture different features, which may confound both expert and statistical quantitative (QSAR) methods. Isolating effects single structural feature made difficult due confounding other functionality as well issues relating determining significance cases concurrent tests large number potential variables with dataset; naïve QSAR model does not predict any be after correction multiple testing. We propose variation Bayesian linear regression estimate each simultaneously yet independently, taking into account combinations present dataset reducing impact testing, showing some have impact. method can used provide validation approaches differences potency between groupings nitrosamines. Structural lead highest lowest isolated using this method, novel assigned categories high accuracy.

Language: Английский

Citations

44
Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite DOI Creative Commons
Joerg Schlingemann,

Céline Boucley,

Sebastian Hickert

et al.

International Journal of Pharmaceutics, Journal Year: 2022, Volume and Issue: 620, P. 121740 - 121740

Published: April 11, 2022

Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue if they exceeded maximum allowable intake 96 ng/day for a medicine with long-term intake. Here, we report results from extensive analysis NDMA content along active pharmaceutical ingredient (API) manufacturing process as well two different drug product processes. Our findings confirm that Metformin API is not significant source found and created at those steps introduce heat nitrite. We demonstrate reduction nitrite excipients effective means to reduce product. Limiting residual dimethylamine has proven be another important factor control leads formation products. Furthermore, historical batches products shown may increase during storage, but reached were shelf-life limiting under study.

Language: Английский

Citations

40
Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals DOI Open Access

Stephen Horne,

Matthew D. Vera,

Laxma R. Nagavelli

et al.

Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 112(5), P. 1166 - 1182

Published: Jan. 1, 2023

Language: Английский

Citations

40
Highly Selective and Sensitive Detection of Nitrite Ion by an Unusual Nitration of a Fluorescent Benzimidazole DOI
Lachhman Singh, Nihar Ranjan

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(5), P. 2745 - 2749

Published: Jan. 30, 2023

Nitrite (NO2-) is a physiologically significant anion having implications for cellular signaling. Here we report our serendipitous discovery of highly selective fluorescence-based nitrite sensing using benzimidazole which stems from hitherto-unknown direct nitration sodium nitrite. Using one- and two-dimensional NMR techniques, elucidate the chemical structures new nitrated benzimidazoles show differences in products conventional with nitric acid. We also its utility robust nitrite-containing samples.

Language: Английский

Citations

40
A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products DOI

Harshita Akkaraju,

Ritik Tatia,

Sayalee Sanjay Mane

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2023, Volume and Issue: 139, P. 105355 - 105355

Published: Feb. 13, 2023

Language: Английский

Citations

40