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Antimicrobial Agents and Chemotherapy Oct 2017The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers...
The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 μg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by and strains. imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections.
Topics: Allylamine; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Aziridines; Candida albicans; Candidiasis; Cell Line; Cell Membrane; Disease Models, Animal; Fibroblasts; Humans; Keratitis; Microbial Sensitivity Tests; Polyethyleneimine; Polylysine; Polymers; Pseudomonas Infections; Pseudomonas aeruginosa; Rabbits; Staphylococcal Infections; Staphylococcus aureus
PubMed: 28784676
DOI: 10.1128/AAC.00469-17 -
Journal of Enzyme Inhibition and... Dec 2023In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide...
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of N- and N,C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
Topics: Humans; Aziridines; Protein Disulfide-Isomerases; Sulfonamides
PubMed: 37070480
DOI: 10.1080/14756366.2022.2158187 -
Nature Communications Jun 2022N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR...
N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR fragments) to olefinic substrates. The exceptional reactivity of most nitrenes, in particular with respect to unimolecular decomposition, prevents general application of nitrene-transfer to the synthesis of N-functionalized aziridines. Here we demonstrate N-aryl aziridine synthesis via 1) olefin aziridination with N-aminopyridinium reagents to afford N-pyridinium aziridines followed by 2) Ni-catalyzed C-N cross-coupling of the N-pyridinium aziridines with aryl boronic acids. The N-pyridinium aziridine intermediates also participate in ring-opening chemistry with a variety of nucleophiles to afford 1,2-aminofunctionalization products. Mechanistic investigations indicate aziridine cross-coupling proceeds via a noncanonical mechanism involving initial aziridine opening promoted by the bromide counterion of the Ni catalyst, C-N cross-coupling, and finally aziridine reclosure. Together, these results provide new opportunities to achieve selective incorporation of generic aryl nitrene equivalents in organic molecules.
Topics: Alkenes; Aziridines; Boronic Acids; Catalysis; Indicators and Reagents; Stereoisomerism
PubMed: 35689000
DOI: 10.1038/s41467-022-31032-w -
Molecules (Basel, Switzerland) Dec 2017In the present paper, we report the synthesis and evaluation of in vitro antimicrobial activities of aziridine-thiourea derivatives. A series of aziridines in reaction...
In the present paper, we report the synthesis and evaluation of in vitro antimicrobial activities of aziridine-thiourea derivatives. A series of aziridines in reaction with isocyanates and isothiocyanates to obtain urea and thiourea derivatives were used. The structures of all new products were confirmed based on spectroscopic data (¹H-NMR, C-NMR, HR-MS). These compounds were screened for their in vitro antimicrobial activity against a panel of Gram-positive and Gram-negative strains of bacteria. Six of the tested compounds appeared to be promising agents against reference strains of , and . Subsequently, compounds exhibiting promising antibacterial activity were tested against twelve clinical isolates of from three different sources of infection. The most bactericidal compounds (MIC = 16-32 µg/mL) showed better antibacterial activity against MRSA than ampicillin and streptomycin. The in vitro cytotoxicity analysis on L929 murine fibroblast and HeLa human tumor cell line using the MTT assay allowed us to select the least toxic compounds for future investigation.
Topics: Anti-Bacterial Agents; Aziridines; Cell Death; Escherichia coli; HeLa Cells; Humans; Indicators and Reagents; Microbial Sensitivity Tests; Staphylococcus aureus; Thiourea; Urea
PubMed: 29295572
DOI: 10.3390/molecules23010045 -
ACS Chemical Biology Feb 2020Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to...
Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to profile PARP engagement in live cells are lacking. Herein, we report the design and application of , the first photoaffinity probe (AfBP) for PARP enzymes based on triple PARP1/2/6 inhibitor , which induces multipolar spindle (MPS) formation in breast cancer cells. is a robust tool for profiling PARP1/2 and is used to profile clinical PARP inhibitor olaparib, identifying several novel off-target proteins. Surprisingly, while can enrich recombinant PARP6 spiked into cellular lysates and inhibits PARP6 in cell-free assays, it does not label PARP6 in intact cells. These data highlight an intriguing biomolecular disparity between recombinant and endogenous PARP6. provides a new approach to expand our knowledge of the targets of this class of compounds and the mechanisms of action of PARP inhibitors in cancer.
Topics: Aziridines; Cell Line, Tumor; Humans; Photoaffinity Labels; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proteomics; Ultraviolet Rays
PubMed: 32017532
DOI: 10.1021/acschembio.9b00963 -
Chemical & Pharmaceutical Bulletin Oct 2005This review highlights author's recent study on allenic compounds. In the first section, organocopper-mediated ring-opening reaction of ethynylaziridines and... (Review)
Review
This review highlights author's recent study on allenic compounds. In the first section, organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes including those which are not accessible by other means, are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes and tandem reaction leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes are presented. The final section presents aziridination and medium-ring formation by intramolecular reaction of bromoallenes, which are scarcely investigated until quite recently. The latter reaction is based on our recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.
Topics: Alkadienes; Aziridines; Catalysis; Copper; Cyclization; Cyclopropanes; Indoles; Molecular Structure; Organometallic Compounds; Palladium; Pyrrolidines
PubMed: 16204973
DOI: 10.1248/cpb.53.1211 -
Molecules (Basel, Switzerland) Feb 2020In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl...
In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45-82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc) under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN to form the corresponding azido amines as single regio- and diastereomers in 90-97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting β-amino alcohols. To obtain a complete series of diastereomeric -diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in S2 reaction (25-58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral -diamines of defined stereochemistries.
Topics: 2,2'-Dipyridyl; Amines; Amino Alcohols; Azides; Aziridines; Diamines; Magnetic Resonance Spectroscopy; Molecular Structure; Stereoisomerism
PubMed: 32046110
DOI: 10.3390/molecules25030727 -
Molecules (Basel, Switzerland) Jan 2016The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification...
Synthesis of Canthardin Sulfanilamides and Their Acid Anhydride Analogues via a Ring-Opening Reaction of Activated Aziridines and Their Associated Pharmacological Effects.
The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i-k, 11l-n, 12o-p, and 16q-s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.
Topics: Anhydrides; Antineoplastic Agents; Aziridines; Cantharidin; Cell Line, Tumor; Cell Survival; HL-60 Cells; Humans; Inhibitory Concentration 50; MCF-7 Cells; Oxazoles; Pyrazoles; Pyrimidines; Structure-Activity Relationship; Sulfanilamides; Thiazoles
PubMed: 26784163
DOI: 10.3390/molecules21010100 -
PloS One 2018Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC...
Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 3/7 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies.
Topics: Apoptosis; Aziridines; Cell Line, Tumor; Cell Proliferation; Dexamethasone; Glucocorticoids; Humans; Multiple Myeloma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Glucocorticoid; Transcriptional Activation
PubMed: 29738549
DOI: 10.1371/journal.pone.0197000 -
Blood Advances Oct 2021Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have...
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Prospective Studies; Thiotepa; Transplantation, Autologous
PubMed: 34464973
DOI: 10.1182/bloodadvances.2021004779