Progress towards the total synthesis of N-methylwelwitindolinone C isothiocyanate

This thesis focuses on our progress towards the total synthesis of N-methylwelwitindolinone C isothiocyanate 7, commonly called welwistatin. This major alkaloid of the welwitindolinone family, which was isolated from Hapalosiphon welwitschii in 1994, represents a particularly attractive target due to its interesting biological activities (MDR reversing agent) and its challenging structure. Welwistatin possesses a complex bicyclo[4.3.1]decane ring system consisting of four stereogenic centres, three quaternary carbons and two unusual reactive functionalities: the isothiocyanate bridgehead and a vinyl chloride group. Inspired by the synthetic challenge of this complex architecture, the Simpkins group reported an expedient four-step synthesis of its core structure in 2005. Three years later, our group had investigated the reactivity at the bridgehead enolate positions. Taking inspiration from this previous work, we successfully synthesised bridgehead alkene 126. The other features present on welwistatin 7 were then investigated and enone 198 was obtained. Facing some difficulties on the model system 88, we turned our attention towards the synthesis of tetracycle 170, possessing the gem-dimethyl at the position C$_{16}$, and its subsequent functionalisation

Developing and implementing a novel mentorship model (4+ 1) for maternal, newborn and child health in Rwanda

BACKGROUND: There are a number of factors that may contribute to high mortality and morbidity of women and newborns in low-income countries. These include a shortage of competent health care providers (HCP) and a lack of sufficient continuous professional development (CPD) opportunities. Strengthening the skills and building the capacity of HCP involved in the provision of maternal, newborn and child health (MNCH) is essential to ensure quality care for mothers, newborns and children. To address this challenge in Rwanda, mentorship of HCPs was identified as an approach that could help build capacity, improve the provision of care and accelerate the reduction in maternal and neonatal mortality and morbidity. In this paper, we describe the development and implementation of a novel mentorship model named Four plus One (4 METHODS: The mentorship model built on the basis of inter-professional collaboration (IPC) was developed in early 2017 through consultations with different key actors. The design phase included refresher courses in specific skills and training course on mentoring. Field visits were conducted in 10 hospitals from June 2017 to February 2020. Hospital management teams (MT) were involved in the development and implementation of this mentorship model to ensure ownership of the program. RESULTS: Upon completion of planned visits to each hospital, a total of 218 HCPs were involved in the process. Reports prepared by mentors upon each mentorship visit and compiled by Training Support and Access Model (TSAM) for MNCH\u27CPD team, highlighted the mothers and newborns who were saved by both mentors and mentees. Also, different logbooks of mentees showed how the capacity of staff was strengthened, thereby suggesting effectiveness of the model. Through different mentorship coordination meetings, the model was much appreciated by the MTs of hospitals, especially the IPC component of the model and confirmed the program \u27effectiveness. CONCLUSION: The initiation of a mentorship model built on IPC together with the involvement of the leadership of the hospital may be the cause effect of reduction of specific mortality and improve MNCH in low resource settings even when there are a limited number of specialists in the health facilities

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine

Behavioural and Autonomic Regulation of Response to Sensory Stimuli among Children: A Systematic Review of Relationship and Methodology

Background. Previous studies have explored the correlates of behavioural and autonomic regulation of response to sensory stimuli in children; however, a comprehensive review of such relationship is lacking. This systematic review was performed to critically appraise the current evidence on such relationship and describe the methods used in these studies. Methods. Online databases were systematically searched for peer-reviewed, full-text articles in the English language between 1999 and 2016, initially screened by title and abstract, and appraised and synthesized by two independent review authors. Results. Fourteen Level III-3 cross-sectional studies were included for systematic review, among which six studies explored the relationship between behaviour and physiological regulation of responses to sensory stimuli. Three studies reported significant positive weak correlations among ASD children; however, no correlations were found in typically developing children. Methodological differences related to individual differences among participants, measures used, and varied laboratory experimental setting were noted. Conclusion. This review suggests inconclusive evidence supporting the relationship between behavioural and physiological regulation of responses to sensory stimuli among children. Methodological differences may likely have confounded the results of the current evidence. We present methodological recommendations to address this matter for future researches. This trial is registered with PROSPERO registration number CRD42016043887

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo