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Journal of Pharmaceutical Sciences May 2023This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures,...
This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions and the challenges to determine compound-specific AIs based on data available or read-across approaches for these nitrosamines and their acceptance by health authorities. Our data indicate that the presence of nitrosamines in pharmaceuticals is likely more prevalent than originally expected. In total, 40.4 % of the analyzed APIs and 29.6 % of the API impurities are potential nitrosamine precursors. Most structures identified through our workflow could form complex API-related nitrosamines, so-called nitrosamine drug substance related impurities (NDSRIs), although we also found structures that could release the well-known small and potent nitrosamines NDMA, NDEA, and others. Due to common structural motifs including secondary or tertiary amine moieties, whole essential drug classes such as beta blockers and ACE inhibitors are at risk. To avoid the risk of drug shortages or even the complete loss of therapeutic options, it will be essential that the well-established ICH M7 principles remain applicable for nitrosamines and that that the industry and regulatory authorities keep an open communication not only about the science but also to make sure there is a good balance between risk and benefit to patients.
Topics: Humans; Nitrosamines; Amines; Pharmaceutical Preparations
PubMed: 36402198
DOI: 10.1016/j.xphs.2022.11.013 -
Molecules (Basel, Switzerland) May 2022-dealkylation, the removal of an -alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of... (Review)
Review
-dealkylation, the removal of an -alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. -dealkylation of amines is also an important in vivo metabolic pathway in the metabolism of xenobiotics. Identification and synthesis of drug metabolites such as -dealkylated metabolites are necessary throughout all phases of drug development studies. In this review, different approaches for the -dealkylation of amines including chemical, catalytic, electrochemical, photochemical and enzymatic methods will be discussed.
Topics: Amines; Dealkylation
PubMed: 35630770
DOI: 10.3390/molecules27103293 -
Molecules (Basel, Switzerland) Jun 2021Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of... (Review)
Review
Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of improving selectivity and mildness of the reaction conditions, preserve protein integrity, and fulfill all the increasing requirements of the modern applications of protein conjugates. The targeting of the protein N-terminal alpha-amine group appears a convenient solution to the issue, emerging as a useful and unique reactive site universally present in each protein molecule. Herein, we provide an updated overview of the methodologies developed until today to afford the selective modification of proteins through the targeting of the N-terminal alpha-amine. Chemical and enzymatic strategies enabling the selective labeling of the protein N-terminal alpha-amine group are described.
Topics: Amines; Azides; Binding Sites; Click Chemistry; Molecular Probe Techniques; Protein Domains; Proteins
PubMed: 34207845
DOI: 10.3390/molecules26123521 -
Molecules (Basel, Switzerland) Dec 2021After being rather neglected as a research field in the past, carbonic anhydrase activators (CAAs) were undoubtedly demonstrated to be useful in diverse pharmaceutical... (Review)
Review
After being rather neglected as a research field in the past, carbonic anhydrase activators (CAAs) were undoubtedly demonstrated to be useful in diverse pharmaceutical and industrial applications. They also improved the knowledge of the requirements to selectively interact with a CA isoform over the others and confirmed the catalytic mechanism of this class of compounds. Amino acid and amine derivatives were the most explored in in vitro, in vivo and crystallographic studies as CAAs. Most of them were able to activate human or non-human CA isoforms in the nanomolar range, being proposed as therapeutic and industrial tools. Some isoforms are better activated by amino acids than amines derivatives and the stereochemistry may exert a role. Finally, non-human CAs have been very recently tested for activation studies, paving the way to innovative industrial and environmental applications.
Topics: Amines; Amino Acids; Animals; Carbonic Anhydrases; Enzyme Activation; Enzyme Activators; Humans; Models, Molecular; Protein Isoforms
PubMed: 34885917
DOI: 10.3390/molecules26237331 -
Journal of Food Protection Sep 2021Histamine is a biogenic amine and a food safety hazard, and it is the only biogenic amine regulated by statute or hazard analysis and critical control point guidance.... (Review)
Review
Histamine is a biogenic amine and a food safety hazard, and it is the only biogenic amine regulated by statute or hazard analysis and critical control point guidance. This article reviews the regulations for histamine levels in fish in countries around the world, including maximum limits or levels and sampling procedures in different fish preparations. The maximum histamine levels, sampling plans, and fish products are listed. The country-by-country regulations for maximum histamine acceptance levels in some food products vary by a factor of 8, from 50 ppm in some countries to a maximum of 400 ppm in other countries. For similar food products, the maximum histamine levels vary by a factor of 4 (from 50 ppm to 200 ppm) in, for example, fresh tuna. The country-by-country sampling plans vary widely as well, and these, too, are covered in detail.
Topics: Animals; Biogenic Amines; Fish Products; Fishes; Histamine; Tuna
PubMed: 33984131
DOI: 10.4315/JFP-21-129 -
Chemistry, An Asian Journal Jun 2022Alkene amino(hetero)arylation presents a highly efficient and straightforward strategy for direct installation of amino groups and heteroaryl rings across a double bond... (Review)
Review
Alkene amino(hetero)arylation presents a highly efficient and straightforward strategy for direct installation of amino groups and heteroaryl rings across a double bond simultaneously. An extensive array of practical transformations has been developed via alkene difunctionalization approach to access a broad range of medicinally valuable (hetero)arylethylamine motifs. This review presents recent progress in 1,2-amino(hetero)arylation of alkenes organized in three different modes. First, intramolecular transformations employing C, N-tethered alkenes will be introduced. Next, two-component reactions will be discussed with different combination of precursors, N-tethered alkenes and external aryl precursor, C-tethered alkenes and external amine precursor, or C, N-tethered reagents, and alkenes. Last, three-component intermolecular amino(hetero)arylation reactions will be covered.
Topics: Alkenes; Amination; Amines; Catalysis
PubMed: 35460596
DOI: 10.1002/asia.202200215 -
Molecules (Basel, Switzerland) Jun 2022In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal,... (Review)
Review
In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal, catalyzed, or noncatalyzed reaction conditions. The aforementioned reactions in the aim to prepare basic five-, six-, organometallic heterocyclic-membered systems and/or their fused analogs. This review article also provides a report on the developed methods describing the synthesis of various heterocycles from organic azides, especially those reported in recent papers (till 2020). At the outset, this review groups the synthetic methods of organic azides into different categories. Secondly, the review deals with the functionality of the azido group in chemical reactions. This is followed by a major section on the following: (1) the synthetic tools of various heterocycles from the corresponding organic azides by one-pot domino reaction; (2) the utility of the chosen catalysts in the chemoselectivity favoring C-H and C-N bonds; (3) one-pot procedures (i.e., Ugi four-component reaction); (4) nucleophilic addition, such as Aza-Michael addition; (5) cycloaddition reactions, such as [3+2] cycloaddition; (6) mixed addition/cyclization/oxygen; and (7) insertion reaction of C-H amination. The review also includes the synthetic procedures of fused heterocycles, such as quinazoline derivatives and organometal heterocycles (i.e., phosphorus-, boron- and aluminum-containing heterocycles). Due to many references that have dealt with the reactions of azides in heterocyclic synthesis (currently more than 32,000), we selected according to generality and timeliness. This is considered a recent review that focuses on selected interesting examples of various heterocycles from the mechanistic aspects of organic azides.
Topics: Amination; Azides; Catalysis; Cyclization; Cycloaddition Reaction
PubMed: 35744839
DOI: 10.3390/molecules27123716 -
Journal of Food Protection Nov 2021This review provides an assessment of heterocyclic amine (HCA) formation and mitigation in processed meat and meat products. HCAs are formed when amino acids react with... (Review)
Review
ABSTRACT
This review provides an assessment of heterocyclic amine (HCA) formation and mitigation in processed meat and meat products. HCAs are formed when amino acids react with creatine during thermal processing of meat and meat products. The formation of HCAs depends on various factors, including the temperature, cooking time, fat contents, and presence of HCA precursors such as water, lipids, and marinades. Additional factors that could affect HCA formation are pH, meat type, and ingredients added during cooking such as antioxidants, amino acids, ions, fat, and sugars, which promote production of HCAs. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, 2-amino-3-methylimidazo-[4,5-f]quinoline, and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline are HCAs of importance because of their link to cancer in humans. More than 25 HCAs have been identified in processed foods. Of these, nine HCAs are possible human carcinogens (group 2B) and one is a probable human carcinogen (group 2A). To mitigate HCA generation during heat processing, various techniques have been used, including recipe variations, adjustments of thermal processing conditions, addition of flavorings, pretreatments such as microwave heating, and addition of naturally occurring and artificial antioxidants.
Topics: Amines; Cooking; Heterocyclic Compounds; Humans; Meat; Meat Products
PubMed: 33956955
DOI: 10.4315/JFP-20-471 -
Biomolecules Nov 2022Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly... (Review)
Review
Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community.
Topics: Humans; Sympathomimetics; Norepinephrine; Tyramine; Amines; Cocaine
PubMed: 36551221
DOI: 10.3390/biom12121793 -
Journal of the American Chemical Society Sep 2021Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological...
Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [Mn(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [Mn(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
Topics: Amination; Amines; Catalysis; Molecular Structure; Coordination Complexes
PubMed: 34514799
DOI: 10.1021/jacs.1c06335