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Expert Opinion on Drug Metabolism &... Jul 2017Apaziquone (also known as EO9 and Qapzola) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill... (Review)
Review
Apaziquone (also known as EO9 and Qapzola) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers.
Topics: Administration, Intravesical; Animals; Antineoplastic Agents; Aziridines; Humans; Indolequinones; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 28637373
DOI: 10.1080/17425255.2017.1341490 -
Leukemia & Lymphoma Dec 2014Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This systematic review summarizes evidence on its effectiveness and safety, in patients with central nervous system [CNS] lymphoma.
METHODS
We searched 3 databases for clinical studies. When feasible, we performed meta-analyses.
RESULTS
We identified 13 eligible studies, none of which with a priori controls. So data synthesis focused on the 226 patients who received thiotepa. Based on pooled estimates, 75.9% of thiotepa-treated patients achieved a complete remission (95% confidence interval [CI] = 67.5-82.8), and 61.7% had a progression-free survival for up to 125 months post-treatment (95% CI = 49.4-72.7). However, 25.5% relapsed, 24.6% experienced infection, and 13.2% experienced neurotoxicity.
DISCUSSION
Thiotepa-based conditioning followed by HSCT may be effective in most CNS lymphoma patients, with a manageable toxicity profile. But adequately powered randomized trials are needed to better evaluate and isolate the effects of thiotepa.
Topics: Central Nervous System Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Myeloablative Agonists; Neoplasm Recurrence, Local; Publication Bias; Thiotepa; Transplantation Conditioning; Treatment Outcome
PubMed: 24491026
DOI: 10.3109/10428194.2014.889825 -
Molecules (Basel, Switzerland) Oct 2017Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed... (Review)
Review
Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed for the synthesis of aziridines, azetidines, pyrrolidines, piperidines, azepanes and azocanes. This review highlights some facile and green synthetic routes for the synthesis of unsubstituted, multisubstituted and highly functionalized saturated cyclic amines including one-pot, microwave assisted, metal-free, solvent-free and in aqueous media.
Topics: Amines; Aziridines; Chemistry Techniques, Synthetic; Cyclization; Green Chemistry Technology; Microwaves; Nitrogen; Piperidines; Pyrrolidines
PubMed: 29023406
DOI: 10.3390/molecules22101691 -
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 -
Journal of Neuro-oncology Mar 2024Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which... (Review)
Review
BACKGROUND
Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which further complicates treatment approaches. Intrathecal (IT) chemotherapy has surfaced as a potential strategy to bypass the blood-brain barrier and address the challenges posed by disseminated disease. Here, we present a review of the safety and efficacy of IT chemotherapy in the treatment of LMD secondary to HGG.
METHODS
A systematic review following PRISMA guidelines was conducted searching PubMed and Embase from January 1995 to September 2022 using specified terms related to IT chemotherapy for LMD. Included articles involved patients diagnosed with LMD from HGG, treated with intrathecal chemotherapy, and provided survival data. Data, including demographics, tumor characteristics, treatment, and survival information, were collected and independently extracted.
RESULTS
A total of 68 patients across 10 clinical studies were diagnosed with LMD from HGG and included in the review. Among these patients, the average age at diagnosis was 44.2 years. GBM was the most common tumor type (n = 58, 85.3%). A majority of the patients presented with recurrent disease (n = 29, 60.4%). The review encompassed various IT chemotherapy regimens, including mafosfamide, thio-TEPA, 5-fluoro-2'-deoxyuridine (FdUrd), methotrexate (MTX), and cytarabine; however, dosages and frequencies were inconsistently reported. The mean progression-free survival (PFS) and overall survival (OS) for this cohort were 7.5 months and 11.7 months, respectively. Common side effects of IT chemotherapy included headaches, nausea, and vomiting, with more severe complications such as myelotoxicity, disseminated intravascular coagulopathy, meningitis, and gastrointestinal toxicity reported in some cases.
CONCLUSION
LMD continues to be an uncommon complication associated with HGG with a poor prognosis. This article provides an overview of the presently available literature on IT chemotherapy for LMD secondary to HGG, and their respective treatment protocols with overall survival attributes. Additional research is warranted to ascertain how to maximize the potential efficacy of IT chemotherapy as a treatment option.
Topics: Humans; Adult; Brain Neoplasms; Glioma; Glioblastoma; Thiotepa; Meninges
PubMed: 38294637
DOI: 10.1007/s11060-024-04582-w -
The Urologic Clinics of North America Feb 2020Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit.... (Review)
Review
Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit. Although the apaziquone trials demonstrate the potential of this new drug, the singular phase 3 trials did not reach their primary endpoint. To date, no new trials are recruiting, so the development of apaziquone seems to have stopped.
Topics: Administration, Intravesical; Antineoplastic Agents; Aziridines; Carcinoma, Transitional Cell; Humans; Indolequinones; Neoplasm Invasiveness; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 31757302
DOI: 10.1016/j.ucl.2019.09.009 -
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 -
Rh(II)-Catalyzed Intermolecular -Aryl Aziridination of Olefins Using Nonactivated N Atom Precursors.Journal of the American Chemical Society Nov 2021The development of the first intermolecular Rh(II)-catalyzed aziridination of olefins using anilines as nonactivated N atom precursors and an iodine(III) reagent as the...
The development of the first intermolecular Rh(II)-catalyzed aziridination of olefins using anilines as nonactivated N atom precursors and an iodine(III) reagent as the stoichiometric oxidant is reported. This reaction requires the transfer of an -aryl nitrene fragment from the iminoiodinane intermediate to a Rh(II) carboxylate catalyst; in the absence of a catalyst only diaryldiazene formation was observed. This -aryl aziridination is general and can be successfully realized by using as little as 1 equiv of the olefin. Di-, tri-, and tetrasubstituted cyclic or acylic olefins can be employed as substrates, and a range of aniline and heteroarylamine N atom precursors are tolerated. The Rh(II)-catalyzed N atom transfer to the olefin is stereospecific as well as chemo- and diastereoselective to produce the -aryl aziridine as the only amination product. Because the chemistry of nonactivated -aryl aziridines is underexplored, the reactivity of -aryl aziridines was explored toward a range of nucleophiles to stereoselectively access privileged 1,2-stereodiads unavailable from epoxides, and removal of the -2,4-dinitrophenyl group was demonstrated to show that functionalized primary amines can be constructed.
Topics: Alkenes; Aniline Compounds; Aziridines; Catalysis; Cyclization; Oxidation-Reduction; Rhodium
PubMed: 34748699
DOI: 10.1021/jacs.1c09229 -
The Journal of Organic Chemistry Jul 2023We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)...
We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf) and 1 equivalent of NaHCO in CHCl is mild and compatible with a range of activating aziridine -substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, di-substituted aziridine silanols give products with an configuration; conversely, di-substituted aziridine silanols give products with a configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.
Topics: Furans; Stereoisomerism; Ethers; Aziridines
PubMed: 37253098
DOI: 10.1021/acs.joc.3c00763 -
Molecules (Basel, Switzerland) Mar 2022A short synthetic route to stereoselective access to -glycosyl-aminoethyl sulfide derivatives has been developed through the reaction of tributhyltin derivatives of...
A short synthetic route to stereoselective access to -glycosyl-aminoethyl sulfide derivatives has been developed through the reaction of tributhyltin derivatives of glycals with aziridinecarboaldehyde and the regioselective ring opening of a chiral aziridine with thiophenol. The absolute configurations of the resulting diastereoisomers were determined by 1H NMR spectroscopy.
Topics: Aziridines; Stereoisomerism; Sulfides
PubMed: 35335129
DOI: 10.3390/molecules27061764