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International Journal of Molecular... Sep 2021Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly... (Review)
Review
Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.
Topics: Aziridines; Carboxylic Acids; Imines; Ketones; Molecular Structure; Stereoisomerism
PubMed: 34576025
DOI: 10.3390/ijms22189861 -
Advances in Experimental Medicine and... 2016DNA methyltransferases (MTases) uniquely combine the ability to recognize and covalently modify specific target sequences in DNA using the ubiquitous cofactor... (Review)
Review
DNA methyltransferases (MTases) uniquely combine the ability to recognize and covalently modify specific target sequences in DNA using the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet). Although DNA methylation plays important roles in biological signaling, the transferred methyl group is a poor reporter and is highly inert to further biocompatible derivatization. To unlock the biotechnological power of these enzymes, two major types of cofactor AdoMet analogs were developed that permit targeted MTase-directed attachment of larger moieties containing functional or reporter groups onto DNA. One such approach (named sequence-specific methyltransferase-induced labeling, SMILing) uses reactive aziridine or N-mustard mimics of the cofactor AdoMet, which render targeted coupling of a whole cofactor molecule to the target DNA. The second approach (methyltransferase-directed transfer of activated groups, mTAG) uses AdoMet analogs with a sulfonium-bound extended side chain replacing the methyl group, which permits MTase-directed covalent transfer of the activated side chain alone. As the enlarged cofactors are not always compatible with the active sites of native MTases, steric engineering of the active site has been employed to optimize their alkyltransferase activity. In addition to the described cofactor analogs, recently discovered atypical reactions of DNA cytosine-5 MTases involving non-cofactor-like compounds can also be exploited for targeted derivatization and labeling of DNA. Altogether, these approaches offer new powerful tools for sequence-specific covalent DNA labeling, which not only pave the way to developing a variety of useful techniques in DNA research, diagnostics, and nanotechnologies but have already proven practical utility for optical DNA mapping and epigenome studies.
Topics: Aziridines; DNA; DNA Methylation; DNA Modification Methylases; Epigenomics; Humans; S-Adenosylmethionine; Staining and Labeling
PubMed: 27826850
DOI: 10.1007/978-3-319-43624-1_19 -
Mini Reviews in Medicinal Chemistry 2016Azaheterocyclic compounds are well-known to have diverse types of biological activity. Among them, azacyclopropanes, commonly referred as aziridines, occupy a prominent... (Review)
Review
Azaheterocyclic compounds are well-known to have diverse types of biological activity. Among them, azacyclopropanes, commonly referred as aziridines, occupy a prominent place in synthetic organic and medicinal chemistry due to its occurrence in natural resources, complexity involved in synthesis due to ring-strain, building blocks in organic synthesis, and its biological properties. Several novel compounds containing aziridine ring have been designed and synthesized recently by medicinal chemists for evaluating their biological profile. A number of compounds are reported as cysteine protease inhibitors, antibacterial, antifungal, anticancer, antileishmanial, and antimalarial agents. This review article summarizes the biological activity of such compounds. The preparation of such compounds is also described.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Aziridines; Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Cysteine Proteinase Inhibitors; Drug Discovery; Fanconi Anemia; Humans; Malaria; Neoplasms; Tubulin Modulators
PubMed: 26156415
DOI: 10.2174/1389557515666150709122244 -
Cancer Treatment Reviews Feb 2016Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage... (Review)
Review
Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.
Topics: Antineoplastic Agents; Cytarabine; Humans; Injections, Spinal; Meningeal Neoplasms; Methotrexate; Neoplasm Seeding; Neoplasm Staging; Radiotherapy; Thiotepa; Treatment Outcome
PubMed: 26827696
DOI: 10.1016/j.ctrv.2015.12.004 -
Accounts of Chemical Research Aug 2020Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain...
Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain energy accommodated in the small ring, (ca. 27 kcal/mol), aziridines undergo ring-opening reactions with a variety of nucleophiles. Therefore, among the synthetic reactions utilizing aziridines, regioselective ring-opening substitutions of aziridines with nucleophiles, such as heteroatomic nucleophiles (e.g., amines, alcohols, and thiols) and carbonaceous nucleophiles (e.g., carbanions, organometallic reagents, and electron-rich arenes), constitute a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. However, the regioselection in such traditional ring-opening substitutions of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging to achieve, especially in the case of Lewis acid-promoted variants. Therefore, the development of robust catalytic ring-opening functionalization methods that enable precise prediction of regioselectivity and stereochemistry is desirable. In this direction, our group focused on the highly regioselective and stereospecific nature of the stoichiometric oxidative addition elementary step of 2-substituted aziridines into Pd(0) complexes in an S2 fashion. In conjunction with the recent advancements in transition-metal-catalyzed cross-coupling reactions of alkyl pseudohalides containing a C(sp)-Q (Q = O, N, S, etc.) bond, aziridines can be used as nonclassical alkyl pseudohalides in regioselective and stereospecific cross-couplings.In this Account, starting from the background of transition-metal-catalyzed ring-opening functionalization of aziridines, our contributions to the palladium-catalyzed regioselective and stereoinvertive cross-couplings of aziridines with organoboron reagents to form C(sp)-C, C(sp)-B, and C(sp)-Si bonds have been compiled. The developed methods allow the syntheses of medicinally important amine compounds, e.g., enantioenriched β-phenethylamines, β-amino acids, and their boron and silyl surrogates, from readily available enantiopure aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst (i.e., Pd/NHC vs Pd/PR systems). Computational studies rationalized the detailed mechanisms of the full catalytic cycle and the regioselectivity and stereospecificity of the reactions. The computational results suggested that the interactions operating between the Pd catalyst and aziridine substrate play important roles in determining the regioselection of the aziridine ring-opening event (i.e., oxidative addition). Also, the computational results rationalized the role of water molecules in promoting the transmetalation step through the formation of a Pd-hydroxide active intermediate. This Account evidences the benefits of synergistic collaborations between experimental and computational methods in developing novel transition-metal-catalyzed cross-coupling reactions.
PubMed: 32786337
DOI: 10.1021/acs.accounts.0c00395 -
National Science Review Oct 2023Aziridines derived from bioactive molecules may have unique pharmacological activities, making them useful in pharmacology (e.g. mitomycin C). Furthermore, the...
Aziridines derived from bioactive molecules may have unique pharmacological activities, making them useful in pharmacology (e.g. mitomycin C). Furthermore, the substitution of the epoxide moiety in epothilone B with aziridine, an analog of epoxides, yielded a pronounced enhancement in its anticancer efficacy. Thus, there is interest in developing novel synthetic technologies to produce aziridines from bioactive molecules. However, known methods usually require metal catalysts, stoichiometric oxidants and/or pre-functionalized amination reagents, causing difficulty in application. A practical approach without a metal catalyst and extra-oxidant for the aziridination of bioactive molecules is in demand, yet challenging. Herein, we report an electro-oxidative flow protocol that accomplishes an oxidant-free aziridination of natural products. This process is achieved by an oxidative sulfonamide/alkene cross-coupling, in which sulfonamide and alkene undergo simultaneous oxidation or alkene is oxidized preferentially. Further anticancer treatments in cell lines have demonstrated the pharmacological activities of these aziridines, supporting the potential of this method for drug discovery.
PubMed: 38059062
DOI: 10.1093/nsr/nwad187 -
International Journal of Molecular... May 2022Highly functionalized aziridines, including compounds with aromatic moieties, are attractive substrates both in synthetic and medical areas of chemistry. There is a... (Review)
Review
Highly functionalized aziridines, including compounds with aromatic moieties, are attractive substrates both in synthetic and medical areas of chemistry. There is a broad and interesting set of synthetic methods for reaching these compounds. Aziridination represents the most explored tool, but there are several other more specific, less well-known, but highly promising approaches. Therefore, the current review focuses on recently described or updated ways to obtain 3-arylated aziridines via different non-aziridination-based synthetic methods, reported mainly since 2000. The presented methods belong to two main directions of synthesis, namely, cyclization of open-chain substrates and rearrangement of other heterocycles. Cyclization of open-chain substrates includes the classic Gabriel-Cromwell type cyclization of halogenated substrates with amines, base-promoted cyclization of activated aminoalcohols (or its analogues), and the oxidative cyclization of β-dicarbonyls. Rearrangements of other heterocycles are presented as the Baldwin rearrangement of 4-isoxazolines, the cycloaddition of 1.3-dipoles or dienes to 2H-azirines, and the addition of C- and N-nucleophiles to the double bond of azirines.
Topics: Aziridines; Azirines; Carboxylic Acids; Cyclization; Ketones; Molecular Structure; Stereoisomerism
PubMed: 35682596
DOI: 10.3390/ijms23115919 -
Organic & Biomolecular Chemistry Jun 2023Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic and pharmacological... (Review)
Review
Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic and pharmacological points of view, many researchers have focused their efforts on the development of new methodologies for the preparation and transformation of these interesting compounds. Over the years, more and more ways to obtain molecules bearing these three-membered functional groups, which are challenging due to their inherent reactivity, have been described. Among them, several are more sustainable. In this review, we report the recent advances in the biological and chemical evolution of aziridine derivatives, in particular, the variety of methodologies described for the synthesis of aziridines and their chemical transformations leading to the formation of interesting derivatives, such as 4-7 membered heterocycles of pharmaceutical interest due to their promising biological activities.
Topics: Aziridines
PubMed: 37218299
DOI: 10.1039/d3ob00424d -
Journal of the American Chemical Society Dec 2020Reaction pathways operative when pyridinophane -oxides are photoirradiated have been studied using time course analyses and careful isolation of photolabile...
Reaction pathways operative when pyridinophane -oxides are photoirradiated have been studied using time course analyses and careful isolation of photolabile intermediates with support from DFT calculations. Based on the data and the isolation of two previously unknown heterocyclophanes, we outline a unified mechanistic scheme that explains competing processes under varying photochemical conditions.
Topics: Aza Compounds; Aziridines; Bridged-Ring Compounds; Density Functional Theory; Molecular Conformation; Oxides; Pyrroles; Ultraviolet Rays
PubMed: 33226803
DOI: 10.1021/jacs.0c09310 -
The Journal of Allergy and Clinical... Mar 2022Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
BACKGROUND
Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
OBJECTIVE
The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.
METHODS
We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.
RESULTS
Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).
CONCLUSIONS
Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 34375618
DOI: 10.1016/j.jaci.2021.07.031