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1.
Life (Basel) ; 14(3)2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38541608

ABSTRACT

Doxorubicin (DOX) is a prevalent anticancer agent; however, it is unfortunately characterized by high cardiotoxicity, myelosuppression, and multiple other side effects. To overcome DOX limitations, two novel pyridoxine-derived doxorubicin derivatives were synthesized (DOX-1 and DOX-2). In the present study, their antitumor activity and mechanism of action were investigated. Of these two compounds, DOX-2, in which the pyridoxine fragment is attached to the doxorubicin molecule via a C3 linker, revealed higher selectivity against specific cancer cell types compared to doxorubicin and a promising safety profile for conditionally normal cells. However, the compound with a C1 linker (DOX-1) was not characterized by selectivity of antitumor action. It was revealed that DOX-2 obstructs cell cycle progression, induces apoptosis via the mitochondrial pathway without the development of necrosis, and showcases antioxidant capabilities, underlining its cell-regulatory roles. In contrast to doxorubicin's DNA-centric mechanism, DOX-2 does not interact with nuclear DNA. Given these findings, DOX-2 presents a new promising direction in cancer therapeutics, which is deserving of further in vivo exploration.

2.
Anal Chem ; 95(49): 17997-18005, 2023 12 12.
Article in English | MEDLINE | ID: mdl-38047582

ABSTRACT

We demonstrate that enzyme-catalyzed reactions can be observed in zero- and low-field NMR experiments by combining recent advances in parahydrogen-based hyperpolarization methods with state-of-the-art magnetometry. Specifically, we investigated two model biological processes: the conversion of fumarate into malate, which is used in vivo as a marker of cell necrosis, and the conversion of pyruvate into lactate, which is the most widely studied metabolic process in hyperpolarization-enhanced imaging. In addition to this, we constructed a microfluidic zero-field NMR setup to perform experiments on microliter-scale samples of [1-13C]fumarate in a lab-on-a-chip device. Zero- to ultralow-field (ZULF) NMR has two key advantages over high-field NMR: the signals can pass through conductive materials (e.g., metals), and line broadening from sample heterogeneity is negligible. To date, the use of ZULF NMR for process monitoring has been limited to studying hydrogenation reactions. In this work, we demonstrate this emerging analytical technique for more general reaction monitoring and compare zero- vs low-field detection.


Subject(s)
Magnetic Resonance Imaging , Pyruvic Acid , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Imaging/methods , Hydrogenation , Pyruvic Acid/metabolism , Fumarates
3.
Commun Chem ; 6(1): 131, 2023 Jun 22.
Article in English | MEDLINE | ID: mdl-37349558

ABSTRACT

Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical tool used in modern science and technology. Its novel incarnation, based on measurements of NMR signals without external magnetic fields, provides direct access to intramolecular interactions based on heteronuclear scalar J-coupling. The uniqueness of these interactions makes each zero-field NMR spectrum distinct and useful in chemical fingerprinting. However, the necessity of heteronuclear coupling often results in weak signals due to the low abundance of certain nuclei (e.g., 15N). Hyperpolarization of such compounds may solve the problem. In this work, we investigate molecules with natural isotopic abundance that are polarized using non-hydrogenative parahydrogen-induced polarization. We demonstrate that spectra of hyperpolarized naturally abundant pyridine derivatives can be observed and uniquely identified whether the same substituent is placed at a different position of the pyridine ring or different constituents are placed at the same position. To do so, we constructed an experimental system using a home-built nitrogen vapor condenser, which allows for consistent long-term measurements, crucial for identifying naturally abundant hyperpolarized molecules at a concentration level of ~1 mM. This opens avenues for future chemical detection of naturally abundant compounds using zero-field NMR.

4.
Chemphyschem ; 22(11): 1042-1048, 2021 06 04.
Article in English | MEDLINE | ID: mdl-33720491

ABSTRACT

An efficient synthesis of vinyl-[1-13 C]pyruvate has been reported, from which 13 C hyperpolarized (HP) ethyl-[1-13 C]pyruvate has been obtained by means of ParaHydrogen Induced Polarization (PHIP). Due to the intrinsic lability of pyruvate, which leads quickly to degradation of the reaction mixture even under mild reaction conditions, the vinyl-ester has been synthesized through the intermediacy of a more stable ketal derivative. 13 C and 1 H hyperpolarizations of ethyl-[1-13 C]pyruvate, hydrogenated using ParaHydrogen, have been compared to those observed on the more widely used allyl-derivative. It has been demonstrated that the spin order transfer from ParaHydrogen protons to 13 C, is more efficient on the ethyl than on the allyl-esterdue to the larger J-couplings involved. The main requirements needed for the biological application of this HP product have been met, i. e. an aqueous solution of the product at high concentration (40 mM) with a good 13 C polarization level (4.8 %) has been obtained. The in vitro metabolic transformation of the HP ethyl-[1-13 C]pyruvate, catalyzed by an esterase, has been observed. This substrate appears to be a good candidate for in vivo metabolic investigations using PHIP hyperpolarized probes.


Subject(s)
Hydrogen/chemistry , Pyruvates/chemistry , Carbon Isotopes , Hydrogenation , Magnetic Resonance Spectroscopy , Molecular Structure , Water/chemistry
5.
Bioorg Med Chem ; 30: 115957, 2021 01 15.
Article in English | MEDLINE | ID: mdl-33373820

ABSTRACT

A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50,MCF-7 < 10 µM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC50 < 5 µM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.


Subject(s)
Antineoplastic Agents/pharmacology , Estradiol/pharmacology , Pyridoxine/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Estradiol/chemical synthesis , Estradiol/chemistry , Humans , Membrane Potential, Mitochondrial/drug effects , Models, Molecular , Molecular Structure , Pyridoxine/chemistry , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
6.
Bioorg Chem ; 104: 104306, 2020 11.
Article in English | MEDLINE | ID: mdl-33011535

ABSTRACT

Many pathogenic bacteria and microscopic fungi form rigid polymicrobial biofilms this way enhancing their resistant to treatment. A series of novel pyridoxine-based quaternary ammonium derivatives of terbinafine characterized by both antifungal and antibacterial activities was designed. The leading compound named KFU-127 exhibits promising antifungal and antibacterial activities against various bacteria and micromycetes in both planktonic and biofilm-embedded forms demonstrating MIC values comparable with those of conventional antifungals and antimicrobials. Similar to other antiseptics like benzalkonium chloride and miramistin, KFU-127 is considerably toxic for eukaryotic cells that limits is application to topical treatment options. On the other hand, KFU-127 reduces the number of viable biofilm-embedded bacteria and C. albicans by 3 orders of magnitude at concentrations 2-4 times lower than those of reference drugs and successfully eradicates S. aureus-C. albicans mixed biofilms. The mechanism of antimicrobial action of KFU-127 is bimodal including both membrane integrity damage and pyridoxal-dependent enzymes targeting. We expect that this bilateral mechanism would result in lower rates of resistance development in both fungal and bacterial pathogens. Taken together, our data suggest KFU-127 as a new promising broad spectrum topical antimicrobial capable of one-shot targeting of bacterial and fungal-bacterial biofilms.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Biofilms/drug effects , Pyridoxine/pharmacology , Quaternary Ammonium Compounds/pharmacology , Terbinafine/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Bacteria/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Fungi/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Structure-Activity Relationship , Terbinafine/chemical synthesis , Terbinafine/chemistry
7.
Front Oncol ; 10: 497, 2020.
Article in English | MEDLINE | ID: mdl-32363160

ABSTRACT

Nuclear Magnetic Resonance allows the non-invasive detection and quantitation of metabolites to be carried out in cells and tissues. This means that that metabolic changes can be revealed without the need for sample processing and the destruction of the biological matrix. The main limitation to the application of this method to biological studies is its intrinsic low sensitivity. The introduction of hyperpolarization techniques and, in particular, of dissolution-Dynamic Nuclear Polarization (d-DNP) and ParaHydrogen Induced Polarization (PHIP) is a significant breakthrough for the field as the MR signals of molecules and, most importantly, metabolites, can be increased by some orders of magnitude. Hyperpolarized pyruvate is the metabolite that has been most widely used for the investigation of metabolic alterations in cancer and other diseases. Although d-DNP is currently the gold-standard hyperpolarization method, its high costs and intrinsically slow hyperpolarization procedure are a hurdle to the application of this tool. However, PHIP is cost effective and fast and hyperpolarized pyruvate can be obtained using the so-called Side Arm Hydrogenation approach (PHIP-SAH). The potential toxicity of a solution of the hyperpolarized metabolite that is obtained in this way is presented herein. HP pyruvate has then been used for metabolic studies on different prostate cancer cells lines (DU145, PC3, and LnCap). The results obtained using the HP metabolite have been compared with those from conventional biochemical assays.

8.
Acta Crystallogr E Crystallogr Commun ; 76(Pt 3): 328-331, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-32148870

ABSTRACT

The title compound represents the thallium(I) salt of a substituted 1,2,5-oxa-diazole, [Tl(C3H3N4O3)] n , with amino- and hydroxamate groups in the 4- and 3- positions of the oxa-diazole ring, respectively. In the crystal, the deprotonated hydroxamate group represents an inter-mediate between the keto/enol tautomers and forms a five-membered chelate ring with the thallium(I) cation. The coordination sphere of the cation is augmented to a distorted disphenoid by two monodentately binding O atoms from two adjacent anions, leading to the formation of zigzag chains extending parallel to the b axis. The cohesion within the chains is supported by π-π stacking [centroid-centroid distance = 3.746 (3) Å] and inter-molecular N-H⋯N hydrogen bonds.

9.
Bioorg Med Chem ; 26(22): 5824-5837, 2018 12 01.
Article in English | MEDLINE | ID: mdl-30429098

ABSTRACT

Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents.


Subject(s)
Alkenes/pharmacology , Antineoplastic Agents/pharmacology , Methane/pharmacology , Pyridoxine/pharmacology , Alkenes/chemical synthesis , Alkenes/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Methane/analogs & derivatives , Models, Molecular , Molecular Structure , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Structure-Activity Relationship
10.
Inorg Chem ; 57(10): 6076-6083, 2018 May 21.
Article in English | MEDLINE | ID: mdl-29741382

ABSTRACT

A pentanuclear CuII5-hydroxo cluster possessing an unusual linear-shaped configuration was formed and crystallized under hydrothermal conditions as a result of the unique cooperation of bridging 1,2,4-triazole ligand ( trans-1,4-cyclohexanediyl-4,4'-bi(1,2,4-triazole) ( tr2 cy)), MoVI-oxide, and CuSO4. This structural motif can be rationalized by assuming in situ generation of {Cu2Mo6O22}4- anions, which represent heteroleptic derivatives of γ-type [Mo8O26]4- further interlinked by [Cu3(OH)2]4+ cations through [ N- N] bridges. The framework structure of the resulting compound [Cu5(OH)2( tr2 cy)2Mo6O22]·6H2O (1) is thus built up from neutral heterometallic {Cu5(OH)2Mo6O22} n layers pillared with tetradentate tr2 cy. Quantum-chemical calculations demonstrate that the exclusive site of the parent γ-[Mo8O26]4- cluster into which CuII inserts corresponds with the site that has the lowest defect ("MoO2 vacancy") formation energy, demonstrating how the local metal-polyoxomolybdate chemistry can express itself in the final crystal structure. Magnetic susceptibility measurements of 1 show strong antiferromagnetic coupling within the Cu5 chain with exchange parameters J1 = -500(40) K (-348(28) cm-1), J2 = -350(10) K (-243(7) cm-1) and g = 2.32(2), χ2 = 6.5 × 10-4. Periodic quantum-chemical calculations reproduce the antiferromagnetic character of 1 and connect it with an effective ligand-mediated spin coupling mechanism that comes about from the favorable structural arrangement between the Cu centers and the OH-, O2-, and tr2 cy bridging ligands.

11.
Biomed Res Int ; 2016: 3864193, 2016.
Article in English | MEDLINE | ID: mdl-27800491

ABSTRACT

A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5-2 µg/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Bacterial Physiological Phenomena/drug effects , Pyridoxine/analogs & derivatives , Quaternary Ammonium Compounds/administration & dosage , Anti-Bacterial Agents/toxicity , Apoptosis/drug effects , Apoptosis/physiology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Pyridoxine/administration & dosage , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Pyridoxine/toxicity , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/toxicity
12.
Int J Pharm ; 461(1-2): 97-104, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24239835

ABSTRACT

A new glycerol-based trifunctional block copolymer (TBC) of propylene oxide and ethylene oxide and its conjugate with succinic acid (TBC-SA) were studied as a drug delivery system and compared with Pluronic L61. TBCs have multiple effects on the plasma membrane of human cells, e.g. increasing its fluidity and ion permeability, inhibiting ATPase activity of efflux transporter P-glycoprotein through reversible membrane destabilization. Such membrane-modulating properties attributed to the unimer form of copolymers increase in the order Pluronic L61≪TBC

Subject(s)
Drug Delivery Systems , Epoxy Compounds/chemistry , Ethylene Oxide/chemistry , Succinic Acid/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adenosine Triphosphatases/metabolism , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Cell Membrane/metabolism , Drug Carriers/chemistry , Hemolysis/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Permeability , Poloxamer/chemistry , Polymers/chemistry
13.
J Biotechnol ; 152(3): 102-7, 2011 Mar 20.
Article in English | MEDLINE | ID: mdl-21295626

ABSTRACT

We propose a new method for the separation of nucleic acids using multi-layered carbon nanotubes (CNTs) as an adsorbent. According to agarose gel electrophoresis, oxidized water-stable CNTs adsorb certain forms of nucleic acids, such as high molecular weight RNA, chromosomal DNA, linear and denatured forms of plasmid DNA. However, CNTs do not adsorb supercoiled form of plasmid DNA. Nucleic acids bound to CNTs can be readily removed by centrifugation whereas supercoiled plasmid DNA remains in solution. Upon the addition of divalent metal ions supercoiled plasmid DNA forms relatively stable complexes with CNTs due to chelation. Thus, new details about association of nucleic acids with CNTs were revealed and stoichiometry of the complexes was estimated. Our results can be used for fine purification of supercoiled plasmid DNA for gene therapy applications as well as manipulation of nucleic acids for biosensor design.


Subject(s)
DNA, Superhelical/isolation & purification , DNA, Superhelical/metabolism , Nanotubes, Carbon/chemistry , Plasmids/isolation & purification , Plasmids/metabolism , Adsorption/drug effects , Animals , Cations, Divalent/pharmacology , DNA/metabolism , Electrodes , Electrophoresis, Agar Gel , Oxidation-Reduction/drug effects , RNA/isolation & purification , Surface Properties/drug effects
14.
Bioelectrochemistry ; 77(1): 37-42, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19574110

ABSTRACT

We studied the electrochemical properties of gold nanoparticles (GNPs) and their complexes with proteins using square-wave voltammetry. Effect of the nanoparticle size and detection procedure was explored upon the oxidation of GNPs on a glassy carbon electrode (GCE). For pre-characterized GNPs of 13, 35 and 78 nm diameter, the oxidation peak potential was +0.98, +1.03 and +1.06 V vs. Ag/AgCl, respectively. The conjugation of GNPs with four different proteins was verified by UV-Vis spectroscopy and atomic force microscopy indicated the formation of protein shells around GNPs. This process hampered the oxidation of GNPs on bare GCE causing pronounced decrease in the current response by an average factor of 72. GCE modification with carbon nanotubes weakly influenced the sensitivity of GNP detection but resulted in a 14.5-fold signal increase averaged for all GNP-protein complexes. The acidic dissolution and electrodeposition of GNPs or their complexes adsorbed on GCE allowed superior signal amplification directly proportional to nanoparticle size. The results are useful for the optimization of voltammetric analysis of GNP-protein complexes and can be extended to the characterization of other metal nanostructures and their complexes with biological components.


Subject(s)
Carbon/chemistry , Gold/chemistry , Metal Nanoparticles/chemistry , Particle Size , Proteins/chemistry , Animals , Biosensing Techniques , Cattle , Electrochemistry , Electrodes , Glass/chemistry , Nanotubes, Carbon/chemistry , Oxidation-Reduction , Proteins/analysis , Rabbits
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