Synthesis of 5-substituted 2'-deoxyuridine-5'-phosphonate analogues and evaluation of their antiviral activity

A small series of 5-(hetero)aryl-modified nucleoside phosphonates was synthesized via an 8-step procedure including a Wittig reaction and Suzuki-Miyaura coupling. An unanticipated anomerization during phosphonate deprotection allowed us to isolate both anomers of the 5-substituted 2'-deoxy-uridine phosphonates and assess their antiviral activity against a broad panel of viruses

Authenticity Revisited : the production, distribution, and consumption of independent folk music in the Netherlands (1993-present)

In ways similar to the 1960s ‘urban folk revival’ – that is, through live performance, mass mediation and sales successes – the genre of folk music rose the surface of the global music industry once more during the first decade of the new millennium. The new labels are hyphenated, as in free-folk, freak-folk, indie-folk and folk-pop, and refer to Americana and electronics as in New Weird America, American Primitivism, and folktronica. Folk music gained momentum in the mid-2000s with acts such as Fleet Foxes, Devendra Banhart, CocoRosie, Bon Iver, and most of all Mumford and Sons, who became the genre’s spearheads. Empirically focused on the position of indie-folk in the Dutch music industry, this Ph.D. thesis investigates how and why folk music – usually ‘dwelling’ under the radar of the mainstream – turned into an industry based genre at the turn of the new millennium. It contributes to a range of recurring themes within the humanities and social sciences, most notably to discussions about digitization and the advent of participatory society, the formation of narrative identity in contemporary modernity, and the shift from snobbism to cultural omnivorousness as a marker of high-status in western societies. Ultimately, it is argued that the re-emergence and re-popularization of folk music in the twenty-first century is part of the emergence of metamodernism as the new cultural dominant, as it responds to the flat and ironic culture we know as ‘postmodernism’ by returning to celebrations of depth, affect and historicity

Stress imaging in patients with a Fontan circulation:A systematic review

Introduction: The aims of this study were to provide an overview of the cardiac stress response in Fontan patients and of the use, safety and clinical value of stress imaging in Fontan patients. Methods: Studies evaluating cardiac function using stress imaging in Fontan patients published up until 12 December 2021 were included in this review. Results: From 1603 potential studies, 32 studies met the inclusion criteria. In total, stress imaging tests of 728 Fontan patients were included. Cardiac function was most often measured using physical stress (61%), all other studies used dobutamine-induced stress. Stroke volume (SV) increased in most studies (71%), mean SV at rest ranged from 27 mL/m2 to 60 mL/m2 versus 27 mL/m2 to 101 mL/m2 during stress, and increased with an average of 4%. Ejection fraction increased in almost all studies, whereas both end-systolic volume and end-diastolic volume decreased during stress. Higher heart rates were obtained with physical stress (82–180) compared to dobutamine induced stress (73–128). Compared to controls, increases in heartrate and SV were lower and end-diastolic volume decreased abnormally in 75% of reporting studies. No major adverse events were reported. Poorer cardiac stress response was related to decreased exercise capacity and higher risk for long-term (adverse) outcomes in Fontan patients. Discussion: Cardiac stress response in Fontan patients differs from healthy subjects, reflected by lower increases in heart rate, diminished preload and decreased cardiac output, especially during higher levels of exercise. Stress imaging is safe, however the added clinical value needs to be investigated in more detail.</p

3'-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase

In an effort to increase the potency and selectivity of earlier identified substrate-based inhibitors of mitochondrial thymidine kinase 2 (TK-2), we now describe the synthesis of new thymidine analogues containing a 4- or 5-substituted 1,2,3-triazol-1-yl substituent at the 3'-position of the 2'-deoxyribofuranosyl ring. These analogues were prepared by Cu- and Ru-catalyzed cycloadditions of 3'-azido-3'-deoxythymidine and the appropriate alkynes, which produced the 1,4- and 1,5-triazoles, respectively. Selected analogues showed nanomolar inhibitory activity for TK-2, while virtually not affecting the TK-1 counterpart. Enzyme kinetics indicated a competitive and uncompetitive inhibition profile against thymidine and the cosubstrate ATP, respectively. This behavior is rationalized by suggesting that the inhibitors occupy the substrate-binding site in a TK-2 ATP complex that maintains the enzyme's active site in a closed conformation through the stabilization of a small lid domain

Synthesis and P2Y₂ receptor agonist activities of uridine 5'-phosphonate analogues

We explored the influence of modifications of uridine 5’-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5’-methylenephosphonates were the reaction of a suitably protected uridine 5’-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki–Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor