-
International Journal of Molecular... Jan 2019Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and...
Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies.
Topics: Cell Line, Tumor; DNA Damage; DNA Repair; Gold; Humans; Metal Nanoparticles; Molecular Structure; Theranostic Nanomedicine
PubMed: 30678294
DOI: 10.3390/ijms20030471 -
Synlett : Accounts and Rapid... Aug 2018The direct, stereospecific amination of alkylboronic and borinic esters can be conducted by treatment of the organoboron compound with methoxyamine and potassium...
The direct, stereospecific amination of alkylboronic and borinic esters can be conducted by treatment of the organoboron compound with methoxyamine and potassium -butoxide. In addition to being stereospecific, this process also enables the direct amination of tertiary boronic esters in an efficient fashion.
PubMed: 30631220
DOI: 10.1055/s-0037-1610172 -
Astronomy and Astrophysics Jan 2018Methoxyamine is a potential interstellar amine that has been predicted by gas-grain chemical models for the formation of complex molecules. The aim of this work is to...
AIMS
Methoxyamine is a potential interstellar amine that has been predicted by gas-grain chemical models for the formation of complex molecules. The aim of this work is to provide direct experimental frequencies of its ground-vibrational state in the millimeter- and submillimeter-wave regions to achieve its detection in the interstellar medium.
METHODS
Methoxyamine was chemically liberated from its hydrochloride salt, and its rotational spectrum was recorded at room temperature from 75 to 480 GHz using the millimeter-wave spectrometer in Valladolid. Many observed transitions revealed - splitting caused by the internal rotation of the methyl group, which had to be treated with specific internal rotation codes.
RESULTS
Over 400 lines were newly assigned for the most stable conformer of methoxyamine, and a precise set of spectroscopic constants was obtained. Spectral features of methoxyamine were then searched for in the Orion KL, Sgr B2, B1-b, and TMC-1 molecular clouds. Upper limits to the column density of methoxyamine were derived.
PubMed: 29983447
DOI: 10.1051/0004-6361/201730744 -
PloS One 2018To investigate the photochemical degradation of trypan blue (TB) and to identify decomposition products.
PURPOSE
To investigate the photochemical degradation of trypan blue (TB) and to identify decomposition products.
METHODS
Defined solution samples of TB and a mixture with lutein/zeaxanthin were exposed to blue light. Thermal degradation processes were ruled out using controls not subjected to irradiation. All samples were analyzed using optical microscopy, UV/Vis spectroscopy, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) spectrometry. Degradation kinetics were determined based on changes in absorbance; intermediates were identified by analyzing mass differences of characteristic fragment ion peaks within the fragmentation patterns, and assignments were verified by NMR.
RESULTS
TB demonstrated a photochemical degradation, which can be triggered by lutein/zeaxanthin. Intermediates vary depending on the presence of lutein/zeaxanthin. The self-sensitized photodegradation of TB occurs under generation of dimethyl sulfate and presumed formation of phenol. In contrast, within the presence of lutein/zeaxanthin the decomposition of TB indicates the formation of methoxyamine and sulfonyl arin. Thermal degradation processes were not observed.
CONCLUSIONS
TB demonstrated a photodegradation that may be triggered by lutein/zeaxanthin and results in the formation of cytotoxic decomposition products. Our findings contribute to understand degradation mechanisms of TB and may elucidate previous clinical and experimental observations of cellular toxicity after TB application.
Topics: Kinetics; Light; Lutein; Photochemistry; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Trypan Blue; Zeaxanthins
PubMed: 29634764
DOI: 10.1371/journal.pone.0195849 -
Oncotarget Oct 2017We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine.
PURPOSE
We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine.
MATERIALS AND METHODS
This was a phase I study with intravenous fludarabine (25 mg/m, days 1-5), and methoxyamine (15 mg/m-120 mg/m, once). A maximum of six cycles were given. Adult patients with relapsed/refractory hematologic malignancies, excluding acute myeloid leukemia, were eligible.
RESULTS
Twenty patients were treated; diagnoses included CLL/SLL ( = 10), follicular lymphoma ( = 3), DLBCL ( = 3), mantle cell lymphoma ( = 1), anaplastic large cell lymphoma ( = 1) and plasma cell myeloma ( = 2). No DLTs were observed and dose escalation reached the maximum planned dose. Hematologic toxicity was frequent; most common grade 3-4 toxicities were lymphopenia (70%), neutropenia (60%), leukopenia (50%) and anemia (40%). Four patients achieved a partial remission and 8 achieved stable disease. The drug combination resulted in increased DNA damage measured with the Comet assay.
CONCLUSIONS
Methoxyamine combined with fludarabine was safe and well tolerated. Hematologic toxicity was comparable to single agent fludarabine. Activity appears to correlate with increased levels of DNA damage. Further studies will examine use of this combination of as part conditioning regimens of stem cell transplant and use of methoxyamine as fludarabine dose-sparing agent.
PubMed: 29108368
DOI: 10.18632/oncotarget.20094 -
Advanced Synthesis & Catalysis Jun 2017The catalytic promiscuity of a ferulic acid decarboxylase from sp. (FDC_s) and phenolic acid decarboxylases (PADs) for the asymmetric conjugate addition of water across...
The catalytic promiscuity of a ferulic acid decarboxylase from sp. (FDC_s) and phenolic acid decarboxylases (PADs) for the asymmetric conjugate addition of water across the C=C bond of hydroxystyrenes was extended to the N-, C- and S-nucleophiles methoxyamine, cyanide and propanethiol to furnish the corresponding addition products in up to 91% . The products obtained from the biotransformation employing the most suitable enzyme/nucleophile pairs were isolated and characterized after optimizing the reaction conditions. Finally, a mechanistic rationale supported by quantum mechanical calculations for the highly ()-selective addition of cyanide is proposed.
PubMed: 28713228
DOI: 10.1002/adsc.201700247 -
European Journal of Medicinal Chemistry Sep 2017As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative...
As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative mechanisms of action. Herein, we report the synthesis of a series of ciprofloxacin-nitroxide conjugates and their corresponding methoxyamine derivatives in high yield. This was achieved by linking various nitroxides or methoxyamines to the secondary amine of the piperazine ring of ciprofloxacin using amide bond coupling. Biological evaluation of the prepared compounds on preformed P. aeruginosa biofilms in flow cells revealed substantial dispersal with ciprofloxacin-nitroxide hybrid 25, and virtually complete killing and removal (94%) of established biofilms in the presence of ciprofloxacin-nitroxide hybrid 27. Compounds 25-28 were shown to be non-toxic in both human embryonic kidney 293 (HEK 293) cells and human muscle rhabdomyosarcoma (RD) cells at concentrations up to 40 μM. Significantly, these hybrids demonstrate the potential of antimicrobial-nitroxide agents to overcome the resistance of biofilms to antimicrobials via stimulation of biofilm dispersal or through direct cell killing.
Topics: Anti-Bacterial Agents; Biofilms; Cell Line, Tumor; Ciprofloxacin; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Microbial Sensitivity Tests; Molecular Structure; Nitrogen Oxides; Pseudomonas aeruginosa; Structure-Activity Relationship
PubMed: 28709125
DOI: 10.1016/j.ejmech.2017.06.058 -
Cell Journal 2017This study intended to observe the effects of methoxyamine (Mx) on cytotoxic effects and DNA damage caused by 5-Fluorouracil (5-FU) in combination with gamma radiation...
OBJECTIVE
This study intended to observe the effects of methoxyamine (Mx) on cytotoxic effects and DNA damage caused by 5-Fluorouracil (5-FU) in combination with gamma radiation in a human colon cancer cell line, HT29.
MATERIALS AND METHODS
In this experimental study, HT29 cells were cultured as a monolayer and treated with different concentrations of 5-FU along with 1 mM Mx for 24 hours. Next, the cells were irradiated with 2 Gy gamma radiation. After the treatments, we assessed for DNA damage, cytotoxicity, and viability by alkaline comet, clonogenic survival, and trypan blue dye exclusion assays.
RESULTS
Cytotoxicity and DNA damage increased with increasing 5-FU concentration. The 1 mM Mx concentration had no significant effect on cytotoxicity and DNA damage from 5-FU; however, it increased the cytotoxic and genotoxic effects of different concentrations of 5-FU when used in combination with 2 Gy gamma radiation.
CONCLUSION
Mx combined with 5-FU enhanced the radiosensitivity of colon cancer cells.
PubMed: 28670521
DOI: 10.22074/cellj.2016.4295 -
Biochemistry Nov 2016The important industrial and environmental carcinogen 1,3-butadiene (BD) forms a range of adenine adducts in DNA, including N-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine...
The important industrial and environmental carcinogen 1,3-butadiene (BD) forms a range of adenine adducts in DNA, including N-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N-HB-dA), 1,N-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine (1,N-HMHP-dA), and N,N-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N,N-DHB-dA). If not removed prior to DNA replication, these lesions can contribute to A → T and A → G mutations commonly observed following exposure to BD and its metabolites. In this study, base excision repair of BD-induced 2'-deoxyadenosine (BD-dA) lesions was investigated. Synthetic DNA duplexes containing site-specific and stereospecific (S)-N-HB-dA, (R,S)-1,N-HMHP-dA, and (R,R)-N,N-DHB-dA adducts were prepared by a postoligomerization strategy. Incision assays with nuclear extracts from human fibrosarcoma (HT1080) cells have revealed that BD-dA adducts were recognized and cleaved by a BER mechanism, with the relative excision efficiency decreasing in the following order: (S)-N-HB-dA > (R,R)-N,N-DHB-dA > (R,S)-1,N-HMHP-dA. The extent of strand cleavage at the adduct site was decreased in the presence of BER inhibitor methoxyamine and by competitor duplexes containing known BER substrates. Similar strand cleavage assays conducted using several eukaryotic DNA glycosylases/lyases (AAG, Mutyh, hNEIL1, and hOGG1) have failed to observe correct incision products at the BD-dA lesion sites, suggesting that a different BER enzyme may be involved in the removal of BD-dA adducts in human cells.
Topics: Animals; Butadienes; Cell Line; Cell Line, Tumor; Cricetinae; Cricetulus; DNA Repair; Deoxyadenosines; Humans
PubMed: 27552084
DOI: 10.1021/acs.biochem.6b00553 -
Molecules (Basel, Switzerland) Jun 2016As bacterial biofilms are often refractory to conventional antimicrobials, the need for alternative and/or novel strategies for the treatment of biofilm related...
As bacterial biofilms are often refractory to conventional antimicrobials, the need for alternative and/or novel strategies for the treatment of biofilm related infections has become of paramount importance. Herein, we report the synthesis of novel hybrid molecules comprised of two different hindered nitroxides linked to the piperazinyl secondary amine of ciprofloxacin via a tertiary amine linker achieved utilising reductive amination. The corresponding methoxyamine derivatives were prepared alongside their radical-containing counterparts as controls. Subsequent biological evaluation of the hybrid compounds on preformed P. aeruginosa flow cell biofilms divulged significant dispersal and eradication abilities for ciprofloxacin-nitroxide hybrid compound 10 (up to 95% eradication of mature biofilms at 40 μM). Importantly, these hybrids represent the first dual-action antimicrobial-nitroxide agents, which harness the dispersal properties of the nitroxide moiety to circumvent the well-known resistance of biofilms to treatment with antimicrobial agents.
Topics: Anti-Bacterial Agents; Biofilms; Ciprofloxacin; Microbial Sensitivity Tests; Molecular Structure; Nitric Oxide; Pseudomonas aeruginosa
PubMed: 27355936
DOI: 10.3390/molecules21070841