Spin-spin coupling constants 13C-15N and 1H-15N in the investigation of azido-tetrazole tautomerism in a series of 2-azidopyrimidines

A new method was developed for the investigation of an azido-tetrazole equilibrium based on using a complex analysis of 13C-15N and 1H-15N spin-spin coupling constants. The use of this approach became possible due to the selective inclusion of 15N isotopes into the structures of 2-azidopyrimidines and their cyclic analogs tetrazolo[1,5-a]pyrimidines. © 2013 Springer Science+Business Media New York

Long-range 1H-15N J couplings providing a method for direct studies of the structure and azide-tetrazole equilibrium in a series of azido-1,2,4-triazines and azidopyrimidines

The selectively 15N labeled azido-1,2,4-triazine 2*A and azidopyrimidine 4*A were synthesized by treating hydrazinoazines with 15N-labeled nitrous acid. The synthesized compounds were studied by 1H, 13C, and 15N NMR spectroscopy in DMSO, TFA, and DMSO/TFA solutions, where the azide-tetrazole equilibrium could lead to the formation of two tetrazoles (T, T′) and one azide (A) isomer for each compound. The incorporation of the 15N label led to the appearance of long-range 1H-15N coupling constants (JHN), which can be measured easily by using amplitude-modulated 1D 1H spin-echo experiments with selective inversion of the 15N nuclei. The observed JHN patterns enable the unambiguous determination of the mode of fusion between the azole and azine rings in the two groups of tetrazole isomers (2*T′, 4*T′ and 2*T, 4*T), even for minor isoforms with a low concentration in solution. However, the azide isomers (2*A and 4*A) are characterized by the absence of detectable J HN coupling. The analysis of the JHN couplings in 15N-labeled compounds provides a simple and efficient method for direct NMR studies of the azide-tetrazole equilibrium in solution. © 2013 American Chemical Society

Antiviral drug Triazavirin, selectively labeled with 2H, 13C, and 15N stable isotopes. Synthesis and properties

[Figure not available: see fulltext.] Isotope-labeled antiviral drug Triazavirin containing 2H, 13C, and 15N atoms in its structure has been synthesized. 13C2H3I and KS13CN served as donors of 13C isotopes. The use of 13С-MeI containing 2H atoms made it possible to additionally incorporate deuterium labels into the structure of the compound. The 15N atoms were incorporated using 15N-enriched sodium nitrite, aminoguanidine carbonate, and ethyl nitroacetate. The resulting 2H3,13C2,15N3-Triazavirin was characterized by NMR spectroscopy. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.This work was supported by the Russian Foundation for Basic Research (grant 20-03-00842) and the Ministry of Science and Higher Education of the Russian Federation (project No. FEUZ-2020-0058 (N687.42B.223/20))

Betaine–N-Heterocyclic Carbene Interconversions of Quinazolin-4-One Imidazolium Mesomeric Betaines. Sulfur, Selenium, and Borane Adduct Formation

Reaction of N-alkylated imidazoles with 2-chloro-4-quinazolinone gave mesomeric betaines, 2-(1-alkyl-1H-imidazolium-3-yl)quinazolin-4-olates, for which three tautomeric forms of N-heterocyclic carbenes (NHCs) can be formulated, in addition to an anionic NHC after deprotonation. The NHC tautomers were trapped with sulfur, selenium, triethylborane, and triphenylborane as thiones, selenones and borane adducts, respectively. We obtained two isomers of the cyclic borane adducts, diazaboroloquinazolinones with [1,5-a] and [5,1-b]-type fusion between the quinazolinone and the diazaborole rings. They correspond to two different NHC tautomers and to the anionic NHC derived thereof. The third NHC tautomer was trapped as a non-cyclic adduct with tris(pentafluorophenyl)borane by coordination to the quinazoline oxygen atom. 2D 1H-15N HMBC experiments of 15N-labeled quinazolinone fragments, quantitative measurements of long-range 1H-15N coupling constants (JHN), and five X-ray single crystal analyses have been carried out for the structure elucidations and to gain insight into the NMR spectroscopic properties of these compounds. © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.Russian Foundation for Basic Research, RFBR: 17-03-01029Deutscher Akademischer Austauschdienst, DAADMinistry of Education and Science of the Russian Federation, Minobrnauka: 4.6351.2017/8.9This work was supported by the Russian Ministry of Education and Science (State contract 4.6351.2017/8.9) and the Russian Foundation for Basic Research (grant 17-03-01029). Single crystal X-ray analysis of 23b was performed at the User Facilities Centers of IGIC RAS within the State Assignment on Fundamental Research to the Kurnakov Institute of General and Inorganic Chemistry. We thank the Deutscher Akademischer Austauschdienst DAAD for the financial support of the internship of S. D. at Clausthal University of Technology, Germany

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Secreted Isoform of Human Lynx1 (SLURP-2):Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a ‘three-finger’ fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC(50) ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the ‘classical’ orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs