Neodymium isotopes in peat reveal past local environmental disturbances

Funding The Stawek profile radiocarbon dating and investigation and neodymium measurements were financed by the National Science Centre, Poland, grants no. 2019/03/X/ST10/00849 and 2020/39/D/ST10/00641. The Głęboczek profile radiocarbon dating and investigation were financed by the National Science Centre, Poland, grant no. 2015/17/B/ST10/01656.Peer reviewedPublisher PD

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d

Mass spectrometry based identification of geometric isomers during metabolic stability study of a new cytotoxic sulfonamide derivatives supported by quantitative structure-retention relationships.

A set of 15 new sulphonamide derivatives, presenting antitumor activity have been subjected to a metabolic stability study. The results showed that besides products of biotransformation, some additional peaks occurred in chromatograms. Tandem mass spectrometry revealed the same mass and fragmentation pathway, suggesting that geometric isomerization occurred. Thus, to support this hypothesis, quantitative structure-retention relationships were applied. Human liver microsomes were used as an in vitro model of metabolism. The biotransformation reactions were tracked by liquid chromatography assay and additionally, fragmentation mass spectra were recorded. In silico molecular modeling at a semi-empirical level was conducted as a starting point for molecular descriptor calculations. A quantitative structure-retention relationship model was built applying multiple linear regression based on selected three-dimensional descriptors. The studied compounds revealed high metabolic stability, with a tendency to form hydroxylated biotransformation products. However, significant chemical instability in conditions simulating human body fluids was noticed. According to literature and MS data geometrical isomerization was suggested. The developed in sillico model was able to describe the relationship between the geometry of isomer pairs and their chromatographic retention properties, thus it supported the hypothesis that the observed pairs of peaks are most likely geometric isomers. However, extensive structural investigations are needed to fully identify isomers' geometry. An effort to describe MS fragmentation pathways of novel chemical structures is often not enough to propose structures of potent metabolites and products of other chemical reactions that can be observed in compound solutions at early drug discovery studies. The results indicate that the relatively non-expensive and not time- and labor-consuming in sillico approach could be a good supportive tool assisting the identification of cis-trans isomers based on retention data. This methodology can be helpful during the structural identification of biotransformation and degradation products of new chemical entities--potential new drugs

Chemical structures of the 15 studied compounds.

<p>Chemical structures of the 15 studied compounds.</p

Summary of retention data obtained for 15 studied compounds and their isomers.

<p>Summary of retention data obtained for 15 studied compounds and their isomers.</p

3-dimentional structures of compound 1 isomers obtained after optimization in the HyperChem software.

<p>3-dimentional structures of compound 1 isomers obtained after optimization in the HyperChem software.</p

MS/MS fragmentation spectrum of protonated compound 14 (m/z 471, A) and metabolite M1 (m/z 587, B) along with proposed structures of formed fragment ions.

<p>MS/MS fragmentation spectrum of protonated compound 14 (m/z 471, A) and metabolite M1 (m/z 587, B) along with proposed structures of formed fragment ions.</p

Summary of metabolic stability assay.

<p>Summary of metabolic stability assay.</p

Common ions present in MS/MS fragmentation spectra of compound 14 and its three main biotransformation products.

<p>M1 – hydroxylated metabolite, M2 – debrominated metabolite, M3 – metabolite both hydroxylated and debromianted.</p

Correlation between experimental log k_w values and those predicted by the developed model.

<p>Correlation between experimental log k_w values and those predicted by the developed model.</p