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Molecules (Basel, Switzerland) Jun 2023Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable,...
Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di--butylphenol derivatives , , , and represent potent dual COX-2/5-LO inhibitors. The incorporation of -carborane and further substitution of the -position resulted in four carborane-based di--butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the -carborane analogs , , , and exhibited lower anticancer activity compared to the related di--butylphenols. Interestingly, did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, can be tested in further mechanistic and in vivo studies.
Topics: Humans; Cyclooxygenase 2; Lipoxygenase Inhibitors; Boranes
PubMed: 37299023
DOI: 10.3390/molecules28114547 -
Molecules (Basel, Switzerland) Dec 2020The first nickelacarborane with structure [10',11'-(Py)-3,9'-Ni(1,2-CBH)(7',8'-CBH)] was isolated from the reaction of nickel(IV) bis(dicarbollide) with pyridine. The...
The first nickelacarborane with structure [10',11'-(Py)-3,9'-Ni(1,2-CBH)(7',8'-CBH)] was isolated from the reaction of nickel(IV) bis(dicarbollide) with pyridine. The molecular structure of this complex was determined by single crystal X-ray diffraction. The nickel atom is a common vertex for the -NiCB cluster and the -NCB cluster where it is located together with carbon atoms in the open NiCB pentagonal face. It is assumed that its formation proceeds through the nucleophile-induced removal of the B(6)H vertex followed by rearrangement of the forming 11-vertex cluster, which most likely proceeds through a sequence of closing and opening reactions.
Topics: Boranes; Coordination Complexes; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Nickel; Pyridines
PubMed: 33353172
DOI: 10.3390/molecules25246009 -
Molecules (Basel, Switzerland) Jul 2022Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of...
Lipoxygenases convert polyunsaturated fatty acids into biologically active metabolites such as inflammatory mediators-prostaglandins and leukotrienes. The inhibition of lipoxygenases is increasingly employed in the treatment of cancer. We evaluated the anticancer potential of two novel 5-lipoxygenase inhibitors, named CarbZDNaph and CarbZDChin, which are analogues of the commercially available inhibitor Rev-5901. The in vitro segment of this study was conducted on a mouse colorectal carcinoma cell line-CT26CL25. For an in vivo model, we induced tumors in BALB/c mice by the implantation of CT26CL25 cells, and we treated the animals with potential inhibitors. A 48 h treatment resulted in diminished cell viability. Calculated IC values (half-maximal inhibitory concentrations) were 25 μM, 15 μM and 30 μM for CarbZDNaph, CarbZDChin and Rev-5901, respectively. The detailed analysis of mechanism revealed an induction of caspase-dependent apoptosis and autophagy. In the presence of chloroquine, an autophagy inhibitor, we observed an increased mortality of cells, implying a cytoprotective role of autophagy. Our in vivo experiment reports tumor growth attenuation in animals treated with CarbZDChin. Compounds CarbZDNaph and Rev-5901 lacked an in vivo efficacy. The results presented in this study display a strong effect of compound CarbZDChin on malignant cell growth. Having in mind the important role of inflammation in cancer development, these results have a significant impact and are worthy of further evaluation.
Topics: Animals; Apoptosis; Autophagy; Boranes; Carcinoma; Caspase 3; Cell Line, Tumor; Colonic Neoplasms; Lipoxygenases; Mice; Mice, Inbred BALB C
PubMed: 35889376
DOI: 10.3390/molecules27144503 -
Molecules (Basel, Switzerland) Apr 2023Short peptides containing the Arg-Gly-Asp (RGD) fragment can selectively bind to integrins on the surface of tumor cells and are attractive transport molecules for the...
Short peptides containing the Arg-Gly-Asp (RGD) fragment can selectively bind to integrins on the surface of tumor cells and are attractive transport molecules for the targeted delivery of therapeutic and diagnostic agents to tumors (for example, glioblastoma). We have demonstrated the possibility of obtaining the - and -protected RGD peptide containing 3-amino--carborane and a glutaric acid residue as a linker fragment. The resulting carboranyl derivatives of the protected RGD peptide are of interest as starting compounds in the synthesis of unprotected or selectively protected peptides, as well as building blocks for preparation of boron-containing derivatives of the RGD peptide of a more complex structure.
Topics: Humans; Boranes; Oligopeptides; Peptides; Neoplasms
PubMed: 37110700
DOI: 10.3390/molecules28083467 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2022A robust method for the selective labeling of peptides via manganese(I) catalysis was devised to achieve the C-2 alkenylation of tryptophan containing peptides with...
A robust method for the selective labeling of peptides via manganese(I) catalysis was devised to achieve the C-2 alkenylation of tryptophan containing peptides with 1-ethynyl-o-carboranes. The manganese-catalyzed C-H activation was accomplished with high catalytic efficiency, and featured low toxicity, high functional group tolerance and excellent E-stereoselectivity. This approach unravels a promising tool for the assembly of o-carborane with structurally complex peptides of relevance to applications in boron neutron capture therapy.
Topics: Boranes; Catalysis; Ions; Manganese; Peptides; Tryptophan
PubMed: 35420234
DOI: 10.1002/chem.202200811 -
Angewandte Chemie (International Ed. in... Oct 2022Terminal iron nitrides (Fe≡N) have been proposed as intermediates of Fe-mediated nitrogen fixation, and well-defined synthetic iron nitrides have been characterized in...
Terminal iron nitrides (Fe≡N) have been proposed as intermediates of Fe-mediated nitrogen fixation, and well-defined synthetic iron nitrides have been characterized in high oxidation states, including Fe , Fe , and Fe . This study reports the generation and low temperature characterization of a terminally bound iron(III) nitride, P Fe(N) (P =tris(o-diisopropylphosphinophenyl)borane), which is a proposed intermediate of iron-mediated nitrogen fixation by the P Fe-catalyst system. CW- and pulse EPR spectroscopy (HYSCORE and ENDOR), supported by DFT calculations, help to define a A ground state electronic structure of this C -symmetric nitride species, placing the unpaired spin in a sigma orbital along the B-Fe-N vector; this electronic structure is distinct for an iron nitride. The unusual d -configuration is stabilized by significant delocalization (≈50 %) of the unpaired electron onto the axial boron and nitrogen ligands, with a majority of the spin residing on boron.
Topics: Iron; Ligands; Nitrogen Fixation; Boranes; Boron; Electron Spin Resonance Spectroscopy; Nitrogen
PubMed: 35973965
DOI: 10.1002/anie.202209655 -
Molecules (Basel, Switzerland) Jun 2023The objective of this study is to design and synthesize substituted η-chromium(0) tricarbonyl metal complexes carrying -carborane units as potential boron neutron...
The objective of this study is to design and synthesize substituted η-chromium(0) tricarbonyl metal complexes carrying -carborane units as potential boron neutron capture therapy (BNCT) agents. In this study, 1,2-diphenyl--carborane () units were used as starting materials to generate biologically active species. We investigated how the structural changes of substituted with chromium(0) tricarbonyl affect the biological properties, and 1-(Phenyl-η-chromium(0) tricarbonyl)-2-phenyl--carborane () and 1,2-bis(phenyl-η-chromium(0) tricarbonyl)--carborane () species were produced in moderate yields. The molecular structures of compounds - were identified and established by infrared (IR); H, B, and C nuclear magnetic resonance (NMR) and X-ray crystallography analyses. Crystal structures of 1,2-diphenyl--carborane and the corresponding chromium complexes , , and were obtained. In an in vitro study using B16 and CT26 cancer cells containing the triphenyl--carboranyl chromium(0) complexes and , which we reported previously, compounds and accumulated at higher levels than compounds and . However, the phenylated -carboranyl chromium complexes have been found to be more cytotoxic than -boronophenylalanine (BPA).
Topics: X-Rays; Chromium; Boranes; Boron Compounds; Molecular Structure
PubMed: 37446604
DOI: 10.3390/molecules28134942 -
Chembiochem : a European Journal of... Mar 2019The major pathway for DNA damage following hydrogen atom abstraction from the C5'-position results in direct strand scission and concomitant formation of a...
The major pathway for DNA damage following hydrogen atom abstraction from the C5'-position results in direct strand scission and concomitant formation of a 5'-aldehyde-containing nucleotide (e.g., T-al). We determined that the half-life of alkali-labile T-al in free DNA under physiological conditions varies from 5-12 days. T-al reactivity was examined at three positions within nucleosome core particles (NCPs). β-Elimination increased >2.5-fold when T-al was proximal to the lysine-rich histone H4 tail. No difference in reactivity between free DNA and NCPs was observed when T-al was distal from the histone tails. The position-dependent involvement of histone tails in T-al elimination was gleaned from experiments with sodium cyanoborohydride and histone protein variants. The enhancement of T-al elimination in NCPs is significantly smaller than previously observed for abasic sites. Computational studies comparing elimination from T-al and abasic sites indicate that the barrier for the rate-determining step in the latter is 2.6 kcal mol lower and is stabilized by a hydrogen bond between the C4-hydroxy group and phosphate leaving group. The long lifetime for T-al in NCPs, combined with what is known about its repair suggests that this DNA lesion might pose significant challenges within cells.
Topics: Borohydrides; DNA; Histones; Lysine; Models, Molecular; Nucleic Acid Conformation; Nucleosomes; Oligonucleotides; Oxidation-Reduction
PubMed: 30444560
DOI: 10.1002/cbic.201800663 -
Theranostics 2019Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated...
Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated with cancer progression, leads to uncontrolled platelet activation. Therefore, the aim of our studies was to improve vasoprotection and to decrease platelet activation during progression of mouse mammary gland cancer by concurrent use of CO and NO donors (CORM-A1 and DETA/NO, respectively). : Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. aggregation and activation of platelets were assessed in the blood of healthy donors and breast cancer patients. Moreover, we analyzed the compounds' direct effect on 4T1 mouse and MDA-MB-231 human breast cancer cells proliferation, adhesion and migration . : We have observed antimetastatic effect of combination therapy, which was only transient in orthotopic model. During early stages of tumor progression concurrent use of CORM-A1 and DETA/NO demonstrated vasoprotective ability (decreased endothelin-1, sICAM and sE-selectin plasma level) and downregulated platelets activation (decreased bound of fibrinogen and vWf to platelets) as well as inhibited EMT process. Combined treatment with CO and NO donors diminished adhesion and migration of breast cancer cells and inhibited aggregation as well as TGF-β release from breast cancer patients' platelets . However, antimetastatic effect was not observed at a later stage of tumor progression which was accompanied by increased platelets activation and endothelial dysfunction related to a decrease of VASP level. : The therapy was shown to have antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation and inhibition of EMT process. The effect was more prominent during early stages of tumor dissemination. Such treatment could be applied to inhibit metastasis during the first stages of this process.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Boranes; Carbonates; Cattle; Cell Adhesion; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Disease Progression; Endothelial Cells; Endothelium; Epithelial-Mesenchymal Transition; Female; Humans; Hydrazines; Lung Neoplasms; Mammary Neoplasms, Animal; Mice, Inbred BALB C; Microfilament Proteins; Neoplasm Metastasis; Nitric Oxide; Nitroso Compounds; Phosphoproteins; Phosphorylation; Platelet Activation; Time Factors
PubMed: 31281522
DOI: 10.7150/thno.31461 -
ACS Nano Sep 2022Catalyst activity can depend distinctly on nanoparticle size and shape. Therefore, understanding the structure sensitivity of catalytic reactions is of fundamental and...
Catalyst activity can depend distinctly on nanoparticle size and shape. Therefore, understanding the structure sensitivity of catalytic reactions is of fundamental and technical importance. Experiments with single-particle resolution, where ensemble-averaging is eliminated, are required to study it. Here, we implement the selective trapping of individual spherical, cubic, and octahedral colloidal Au nanocrystals in 100 parallel nanofluidic channels to determine their activity for fluorescein reduction by sodium borohydride using fluorescence microscopy. As the main result, we identify distinct structure sensitivity of the rate-limiting borohydride oxidation step originating from different edge site abundance on the three particle types, as confirmed by first-principles calculations. This advertises nanofluidic reactors for the study of structure-function correlations in catalysis and identifies nanoparticle shape as a key factor in borohydride-mediated catalytic reactions.
Topics: Borohydrides; Catalysis; Fluoresceins; Nanoparticles; Particle Size
PubMed: 36054658
DOI: 10.1021/acsnano.2c06505