Functionalized Rhodium Intercalators for DNA Recognition

A series of rhodium complexes containing the phenanthrenequinone diimine (phi) ligand have been prepared which bind DNA by intercalation and, upon photoactivation, promote DNA strand breaks. In this series, the ancillary, nonintercalating bipyridyl or phenanthroline ligands have been functionalized to yield complexes containing guanidinium, amido, or amino groups arranged with defined stereochemistry for site-specific interaction with the DNA bases. Λ-1-[Rh(MGP)_2phi]^(5+) (MGP = 4-(guanidylmethyl)-1,10-phenanthroline) site-specifically targets the 6-base pair sequence 5‘-CATATG-3‘ with a binding affinity of 1 (±0.5) × 10^8 M^(-1) while Δ-1-[Rh(MGP)_2phi]^(5+) displays an affinity of 5 (±2) × 10^7 M^(-1) for 5‘-CATCTG-3‘. Even though these two isomers target sites which differ by only a single base, binding is highly enantioselective. The specificity is derived chiefly from interactions of the pendant guanidinium groups with the DNA bases. For the racemates of 1-[Rh(GEB)_2phi]^(5+) (GEB = (4-(2-guanidylethyl)-4‘-methyl-2,2‘-bipyridine) and 1-[Rh(GPB)_2phi]^(5+) (GPB = (4-(2-guanidylpropyl)-4‘-methyl-2,2‘-bipyridine), photocleavage patterns also show the strongest site of photocleavage as 5‘-CATCTG-3‘, the target site for Δ-1-[Rh(MGP)_2phi]^(5+). Moreover, consistent with the dominance of the guanidinium groups in establishing specificity, significantly enhanced photocleavage is evident for the 1-positional isomer of these complexes, where the guanidinium moieties are directed toward the DNA (above and below the phi ligand) compared to the 2-isomer, in which the guanidinium groups are directed away from the DNA. In contrast to Λ-1-[Rh(MGP)_2phi]^(5+), Λ-1-[Rh(GEB)_2phi]^(5+) shows little cleavage at 5‘-CATATG-3‘; this sensitivity to linker length likely depends on the mode of recognition of 5‘-CATATG-3‘ involving sequence-dependent unwinding of the DNA site. Analogous site-specificity or isomer-specificity is not evident with the complexes which contain pendant amido or amino functionalities. Instead these complexes appear to resemble the parent, unfunctionalized [Rh(phen)_2phi]^(3+) with respect to recognition. Pendant guanidinium functionalities appear to be particularly advantageous in the construction of small molecules which bind DNA with site-specificity

Contexto bioético de la venta de misoprostol en las farmacias y boticas del Perú

La presente es una investigación bibliográfica y tuvo como objetivos describir, comprender y analizar el contexto bioético de la venta del misoprostol en las farmacias y boticas del Perú. Se analizó la documentación científica así como oficial de instituciones públicas y privadas, nacionales e internacionales, como los riesgos para la salud y vida de la mujer del uso del misoprostol de manera clandestina, la vigencia de este medicamento en las terapias como protector de la mucosa gástrica, su venta en las farmacias y boticas de manera oficial y clandestina. Los resultados indicaron que sí existen por la venta del misoprostol al público transgresiones contra principios bioéticos y regulatorios que ponen en riesgo la vida y la salud de la mujer y del concebido. Las conclusiones proponen alternativas a los problemas bioéticos que plantea este medicamento en su venta en farmacias y boticas del Perú.Tesi

Sequence-Specific DNA Binding by a Rhodium Complex: Recognition Based on Sequence-Dependent Twistability

The chemical construction of small molecules targeted to DNA depends upon the sequence dependent structure of the double helix. Here we describe a new structural element to be considered in the sequence-specific recognition of DNA, sequence-dependent DNA twistability. The importance of sequence-dependent DNA twistability is demonstrated in the DNA recognition properties of a novel synthetic rhodium intercalator, A-1-Rh(MGP)_2phi^(5+). This metallointercalator, containing pendant guanidinium groups, binds in the major groove of DNA at subnanomolar concentrations to the 6 base pair sequence 5'-CAT A TG-3' with enantiospecificity. An essential feature of this recognition is the sequence-specific unwinding of the DNA helix, which permits direct contacts between guanidinium functionalities on the metal complex and guanine residues. Through an assay developed to test for sequence-specific DNA unwinding, a 70 ± 10° unwinding of the sequence 5'-CATATG-3' is established with specific binding by the metal complex. This sequence-dependent twistability may be an essential feature of the recognition of sequences by DNA-binding proteins and may be exploited in future design

Gene expression for biodosimetry and effect prediction purposes: promises, pitfalls and future directions - key session ConRad 2021.

PURPOSE: In a nuclear or radiological event, an early diagnostic or prognostic tool is needed to distinguish unexposed from low- and highly exposed individuals with the latter requiring early and intensive medical care. Radiation-induced gene expression (GE) changes observed within hours and days after irradiation have shown potential to serve as biomarkers for either dose reconstruction (retrospective dosimetry) or the prediction of consecutively occurring acute or chronic health effects. The advantage of GE markers lies in their capability for early (1-3 days after irradiation), high-throughput, and point-of-care (POC) diagnosis required for the prediction of the acute radiation syndrome (ARS). CONCLUSIONS: As a key session of the ConRad conference in 2021, experts from different institutions were invited to provide state-of-the-art information on a range of topics including

Biological impact of iberdomide in patients with active systemic lupus erythematosus

Objectives Iberdomide is a high-Affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). Methods Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. Results Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. Conclusion Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. Trial registration number NCT03161483

Human Radiation Genes.

<p>Human Radiation Genes.</p

CLPA Assay Genes.

<p>CLPA Assay Genes.</p