Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines

NOTICE: This is the peer reviewed version of the following article: Velasco-Rubio, A., Varela J. A., Saá C. (2020). Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines. Adv. Synth. Catal., 362, 22, 4861-4875. [doi: 10.1002/adsc.202000808]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for self-archivingBenzazepines and benzodiazepines, benzofused seven-membered N-heterocycles, compose an important family of natural products and pharmaceuticals. Although certainly important and effectives, classical synthetic methods of these cyclic compounds involve methodologies that often require multistep procedures, with generation of waste materials and lack of sustainability. By contrast, cycloadditions based on transition metal catalyzed C-H bond activations (oxidative annulations) have emerged as appealing strategies for more sustainable synthetic processes. In this review, we focus our attention to describe the state-of-the-art transition-metal catalyzed annulations via C-H activations to benzazepines and benzodiazepines.This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018- 102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019- 2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF)S

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

Background: The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in vitro 60-cell screen. Methods: Over a period of more than twenty years the EORTC—Cancer Research Campaign panel reviewed ~2000 compounds of which 95 were selected for further evaluation. Selected compounds were stepwise developed with clear go/no go decision points using a pharmacologically directed programme. Results: This approach eliminated quickly compounds with unsuitable pharmacological properties. A few compounds went into Phase I clinical evaluation. The lessons learned and many of the principles outlined in the paper can easily be applied to current and future drug discovery and development programmes. Conclusions: Changes in the review panel, restrictions regarding numbers and types of compounds tested in the NCI in vitro screen and the appearance of targeted agents led to the discontinuation of the European NCI programme in 2017 and its transformation into an academic platform of excellence for anticancer drug discovery and development within the EORTC-PAMM group. This group remains open for advice and collaboration with interested parties in the field of cancer pharmacology

Selected aspects of environment protection in the assessment of respondents

W pracy przedstawiono wypowiedzi 685 osób dotyczące ich codziennych działań na rzecz ochrony oraz oceny stanu środowiska w Polsce i warunkujących go czynników. Zdecydowana większość respondentów pochodziła z woj. podkarpackiego, a ich wiek, płeć, poziom wykształcenia oraz deklarowany stopień zainteresowania problematyką ochrony środowiska pełniły rolę determinant ich opinii w powyższym zakresie. W celu sprawdzenia statystycznej istotności zróżnicowania opinii i praktyk badanych osób posłużono się nieparametrycznym testem chi-kwadrat z uwagi na charakter zebranych informacji. Stwierdzono, że głównym źródłem informacji o problematyce ochrony środowiska był Internet. Stan zanieczyszczenia środowiska w Polsce został określony, w przeważającej liczbie przypadków, jako średni, przy czym jako główny powód nieprzestrzegania zasad ochrony środowiska podano bezkarność sprawcy. Najpowszechniejszymi działaniami na rzecz zachowania czystości środowiska okazały się: segregacja odpadów, oszczędne zużycie energii elektrycznej oraz wody, a głównym ograniczeniem zachowań proekologicznych był brak czasu oraz sytuacja finansowa respondentów.The work presents statements of 685 people regarding their everyday activities for the protection and assessment of the condition of the environment in Poland and the factors determining it. The vast majority of respondents came from the province Podkarpackie, and their age, gender, level of education and the declared level of interest in the issues of environmental protection played the role of determinants of their opinion in the above-mentioned field. In order to check the statistical significance of the diversity of opinions and practices of the respondents, a nonparametric Chi-square test was used due to the nature of the collected information. It was found that the main source of information on environmental issues was the Internet. The state of environmental pollution in Poland has been determined, in the majority of cases, as medium, with the perpetrator being impunity for the main reason for non-compliance with environmental protection rules. The most-advanced activities for environmental cleanliness have been proven waste segregation, economical use of electricity and water, and the main limitation of pro-ecological behavior was the lack of time and financial situation of the respondents

Zakres stwierdzony i oczekiwany zawartości metalicznych pierwiastków śladowych w glebach Bieszczadów

Badano zawartość niektórych metalicznych pierwiastków śladowych w glebach Bieszczadów (gleby brunatne kwaśne - poziom Ah i świeże namuły). W oparciu o zakres empiryczny wyznaczono i zaprezentowano zakres oczekiwany zawartości. Zakres ten (95% z uzyskanych wyników) obliczono w sposób następujący: S/SG² do G x SG² (G - średnia geometryczna; SG - odchylenie geometryczne).The contents of some metallic elements in Bieszczady mountain soils (acid brown soils - mineral horizons, fresh alluvial deposit) were described. On the basis of empirically observed range, the expected range was also determined and presented. Baseline values (95% expected ranges) were calculated as follows: S/SG² to G x SG² (G - geometric mean; SG - geometric deviation)

Covalent Bonding of Pyrrolobenzodiazepines (PBDs) to Terminal Guanine Residues within Duplex and Hairpin DNA Fragments.

Pyrrolobenzodiazepines (PBDs) are covalent-binding DNA-interactive agents with growing importance as payloads in Antibody Drug Conjugates (ADCs). Until now, PBDs were thought to covalently bond to C2-NH2 groups of guanines in the DNA-minor groove across a three-base-pair recognition sequence. Using HPLC/MS methodology with designed hairpin and duplex oligonucleotides, we have now demonstrated that the PBD Dimer SJG-136 and the C8-conjugated PBD Monomer GWL-78 can covalently bond to a terminal guanine of DNA, with the PBD skeleton spanning only two base pairs. Control experiments with the non-C8-conjugated anthramycin along with molecular dynamics simulations suggest that the C8-substituent of a PBD Monomer, or one-half of a PBD Dimer, may provide stability for the adduct. This observation highlights the importance of PBD C8-substituents, and also suggests that PBDs may bind to terminal guanines within stretches of DNA in cells, thus representing a potentially novel mechanism of action at the end of DNA strand breaks

HPLC/MS data obtained from interaction of SJG-136 (2) with Hairpin-5.

<p><b>A</b>, HPLC chromatogram showing the annealed Hairpin-5 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152303#pone.0152303.g002" target="_blank">Fig 2</a>) alone at RT 7.64 min; <b>B</b>, HPLC chromatogram after incubation of annealed Hairpin-5 with <b>2</b> for 24 hours, showing approximately 50% conversion to the adduct peak at RT 14.03 min; <b>C</b>, MALDI-TOF spectrum of the adduct at RT 14.03 min from Chromatogram B above. Observed mass of 1:1 <b>2</b>/Hairpin-5 adduct: 6305.1 m/z (theoretical mass: 6305.41 m/z), observed mass of DNA Hairpin-5 alone from Chromatogram <b>A</b>: 5748.3 m/z (theoretical mass: 5748.8 m/z).</p