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

DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways DOI Open Access
Jörg Fahrer, Markus Christmann

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4684 - 4684

Published: Feb. 28, 2023

Nitrosamines occur widespread in food, drinking water, cosmetics, as well tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected impurities various drugs. This is of particular concern are alkylating agents that genotoxic carcinogenic. We first summarize the current knowledge on different sources chemical nature with a focus relevant nitrosamines. Subsequently, we present major DNA alkylation adducts induced by upon their metabolic activation CYP450 monooxygenases. then describe repair pathways engaged adducts, which include base excision repair, direct damage reversal MGMT ALKBH, nucleotide repair. Their roles protection against carcinogenic effects highlighted. Finally, address translesion synthesis tolerance mechanism to adducts.

Language: Английский

Citations

39
Recent advances in covalent organic frameworks (COFs) for wound healing and antimicrobial applications DOI Creative Commons
Fatemeh Mohajer, Ghodsi Mohammadi Ziarani, Alireza Badiei

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(12), P. 8136 - 8152

Published: Jan. 1, 2023

Covalent organic frameworks (COFs) are crystal-like structures such as cartography buildings prepared from appropriately pre-designed construction block precursors and deployed for wound healing purposes.

Language: Английский

Citations

24
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy DOI
Daniel A. DiRocco, Yong‐Li Zhong, Diane N. Le

et al.

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 404 - 412

Published: Feb. 5, 2024

An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor the treatment of Von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency previous supply and commercial routes was encumbered by lengthy 5-step sequence, needed to install chiral benzylic alcohol traditional methods. Identification directed evolution FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled direct enantioselective C–H hydroxylation simple indanone starting material. While this enabling transformation set stage greatly synthesis, several other key innovations were made including development base-metal-catalyzed sulfonylation, KRED-catalyzed dynamic kinetic resolution, facile SNAr reaction in water. Together, these improvements resulted significantly shorter (9 steps) versus route (16 75% reduction process mass intensity (PMI), while also removing reliance on third-row transition metals toxic solvents.

Language: Английский

Citations

10
Food contaminants: Impact of food processing, challenges and mitigation strategies for food security DOI
Arumugam Vignesh,

Thomas Cheeran Amal,

Krishnan Vasanth

et al.

Food Research International, Journal Year: 2024, Volume and Issue: 191, P. 114739 - 114739

Published: July 6, 2024

Language: Английский

Citations

9
Optical and Electrical Dual-Mode Detection of a Carcinogenic Substance Based on Synergy of Liquid Crystals and Ionic Liquids DOI
Li Li,

Yixuan Mei,

Zejun Sun

et al.

ACS Sensors, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Visual, sensitive, and selective detection of carcinogenic substances is highly desired in portable health protection practical medicine production. However, achieving this goal presents significant challenges with the traditional single-mode sensors reported so far, as they have limited sensing mechanisms provide only a single output signal. Here, we report an effective optical electrical dual-mode sensor for visual,

Language: Английский

Citations

1
Method development and validation for determination of N-nitrosamines in pharmaceutical preparations by LC-MS/MS: Application to extractables and leachables studies DOI

Oğuzhan Dalkılıç,

İbrahim Hakkı Demircioğlu,

Saffet Çelik

et al.

Journal of Chromatography A, Journal Year: 2025, Volume and Issue: 1745, P. 465741 - 465741

Published: Jan. 29, 2025

Language: Английский

Citations

1
Re‐Evaluating Acceptable Intake: A Comparative Study of N‐Nitrosomorpholine and N‐Nitroso Reboxetine Potency DOI Creative Commons
Shaofei Zhang, Jennifer Cheung, Jakub Kostal

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

ABSTRACT Establishing regulatory limits for Drug Substance‐Related Impurities (NDSRIs) is challenging due to the limited genotoxicity and carcinogenicity data available many of these impurities, often leading conservative approaches. In this study, we evaluated genotoxic potential two structurally related nitrosamines: N‐nitrosomorpholine (NMOR) N‐nitroso reboxetine. Compared well‐studied NMOR, there little toxicological information Currently, both compounds have an acceptable intake value 127 ng/day, based on a read‐across using NMOR. While tested positive in series vitro vivo assays, found that mutagenic reboxetine was significantly lower than The benchmark dose (BMD) analysis mutagenicity supports 24,000 ng/day Computational studies, carried out quantum‐mechanical CADRE program, were consistent with outcomes, suggesting at or above 1500 comparison prediction supported by computed reactivity hydroxylation step, greater steric hindrance alpha carbons, more facile proton transfer heterolysis toward aldehyde metabolite. presented work can be used refine improve Carcinogenic Potency Categorization Approach (CPCA). It also underscores importance collaboration between authorities, pharmaceutical industry, scientific researchers address risks while avoiding overestimation certain NDSRIs.

Language: Английский

Citations

1
Outlining Key Perspectives for the Advancement of Electrocatalytic Remediation of Nitrate from Polluted Waters DOI
Kenneth Flores, Gabriel Antonio Cerrón-Calle,

Carolina Valdés

et al.

ACS ES&T Engineering, Journal Year: 2022, Volume and Issue: 2(5), P. 746 - 768

Published: May 2, 2022

As nitrate pollution in groundwater continues to escalate, more is being discovered about the detrimental health implications associated with concentrated ingestion. Thus, there a great necessity for effective and sustainable remediation of from water. The electrocatalytic reduction (ERN) has been identified as promising technology respect selective product formation (N2(g) NH3/NH4+), adaptable instrument configurations, compatibility renewable energy sources. Electrocatalysts appreciable selectivity nitrogen gas are importance drinking water applications. On other hand, ammonia-selective catalysts desirable resource recovery. Traditional ERN applications include expensive platinum group metals, which makes widespread utilization this economically unfavorable. Alternatively, research within last five years shown cost-effective catalytic materials such bimetallic systems, graphitic composites, metal oxides, sulfides exhibiting substantial activity/selectivity Future must not only express significant but also be capable stable consistent performance under varying chemistries. Combating electrocatalyst aging fouling processes will key material design efficient continuous long-term operation.

Language: Английский

Citations

36
An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals DOI Creative Commons
Wisut Wichitnithad,

Siriwan Nantaphol,

Kachathong Noppakhunsomboon

et al.

Saudi Pharmaceutical Journal, Journal Year: 2022, Volume and Issue: 31(2), P. 295 - 311

Published: Dec. 24, 2022

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic mutagenic effects patients relying these medications, established specific guidelines risk assessment scenarios proposed control limits for impurities pharmaceuticals. In this review, nitrosation pathways possible root causes of formation pharmaceuticals are discussed. The by national presented. Additionally, a practical science-based strategy implementing well-established is notably reviewed terms an alternative approach product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, novel evaluation predicting investigating amine precursors as powerful prevention addressed.

Language: Английский

Citations

34
N-nitrosamine Mitigation with Nitrite Scavengers in Oral Pharmaceutical Drug Products DOI Creative Commons
Anne-Cécile V. Bayne,

Zdravka Misic,

René T. Stemmler

et al.

Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 112(7), P. 1794 - 1800

Published: April 5, 2023

N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of drug products. One strategy to inhibit formation during manufacture storage involves incorporation nitrite scavengers formulation. Diverse molecules have been tested screening studies including antioxidant vitamins ascorbic acid α-tocopherol, amino acids, other antioxidants used foods or drugs, inclusion into mitigate formation. This review article outlines key considerations oral product formulations.

Language: Английский

Citations

20