9 research outputs found
Versatile Synthesis of 4-Methylidenepyrazolidin-3-ones Using a HornerâWadsworthâEmmons Approach
A new, versatile method for the synthesis of, so far unknown, variously substituted 4-methylidenepyrazolidin-3-ones as potential cytotoxic agents is described. Target compounds were synthesized from the corresponding 4-diethoxyphosphorylpyrazolidin-3-ones which were used as HornerâWadsworthâEmmons Âreagents for the olefination of formaldehyde. 4-Phosphorylpyrazolidin-3-ones were, in turn, obtained starting from the sodium salt of ethyl 2-diethoxyphosphoryl-3-hydroxy-2-propenoate, ethyl 2-acyl-2-diethoxyphosphorylacetates, or 3-methoxy-2-diethoxyphosphorylacrylate and monosubstituted or 1,2-disubstituted hydrazines
Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells
Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 ”M and 5.9 ”M, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents
Classification of Polish Natural Bee Honeys Based on Their Chemical Composition
The targeted quantitative NMR (qNMR) approach is a powerful analytical tool, which can be applied to classify and/or determine the authenticity of honey samples. In our study, this technique was used to determine the chemical profiles of different types of Polish honey samples, featured by variable contents of main sugars, free amino acids, and 5-(hydroxymethyl)furfural. One-way analysis of variance (ANOVA) was performed on concentrations of selected compounds to determine significant differences in their levels between all types of honey. For pattern recognition, principal component analysis (PCA) was conducted and good separations between all honey samples were obtained. The results of present studies allow the differentiation of honey samples based on the content of sucrose, glucose, and fructose, as well as amino acids such as tyrosine, phenylalanine, proline, and alanine. Our results indicated that the combination of qNMR with chemometric analysis may serve as a supplementary tool in specifying honeys
Topology of Ladder Supramolecular Assemblies in Azahetorocyclic Phosphonates: A Structural and Computational Approach
Topologies of ladder packing arrangements
in crystal structures
of five azaheterocyclic phosphonates were characterized by four geometrical
descriptors introduced in the paper. The structural analysis was augmented
by detailed calculations on interactions stabilizing the molecular
assemblies. Intermolecular energies were evaluated using PIXEL and
DFTÂ(M062x-GD3) methods. Additionally, fingerprint plots derived from
the Hirshfeld surfaces were generated for each structure to characterize
the crystal packing arrangement in detail. All structures are stabilized
by the relatively weak hydrogen bonds and nonbonding interactions
involving aromatic rings, i.e., Ï···Ï,
CâH···Ï, and (lp)···Ï
effects. Distribution of the molecular electrostatic potential demonstrates
that positively charged, endocyclic sulfur atoms are prone to chalcogenâchalcogen
(S···O) bonding. Analysis of the supramolecular motifs
shows the lack of a common synthon responsible for the ladder packing
arrangements. However, the striking geometry similarity of all molecules
indicates that ladder packing is based on a shape oriented molecular
recognition and mostly driven by the van der Waals forces. The intermolecular
electrostatic effects are crucial for stabilizing and fixing geometry
of the already formed molecular clusters
Synthesis and structure-activity relationship studies of benzo[b][1,4]oxazin-3(4H)-one analogues as inhibitors of mycobacterial thymidylate synthase
Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure-activity relationships.status: Published onlin
Synthesis and StructureâActivity Relationship Studies of Benzo[ b ][1,4]oxazinâ3(4 H )âone Analogues as Inhibitors of Mycobacterial Thymidylate Synthaseâ X
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