Condensation domain editing of the FR900359 assembly line yields a novel analog amenable to late-stage functionalization.

The natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein-coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure-activity-relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid-phase peptide synthesis. Options for late-stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR-assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold.

Perception of the compatibility of Quebec residency program characteristics with the advanced access model: a cross-sectional study.

BACKGROUND: The advanced access (AA) model is among the most recommended innovations for improving timely access in primary care (PC). AA is based on core pillars such as comprehensive planning for care needs and supply, regularly adjusting supply to demand, optimizing appointment systems, and interprofessional collaborative practices. Exposure of family medicine residents to AA within university-affiliated family medicine groups (U-FMGs) is a promising strategy to widen its dissemination and improve access. Using four AA pillars as a conceptual model, this study aimed to determine the theoretical compatibility of Quebec's university-affiliated clinics' residency programs with the key principles of AA. METHODS: A cross-sectional online survey was sent to the chief resident and academic director at each participating clinic. An overall response rate of 96% (44/46 U-FMGs) was obtained. RESULTS: No local residency program was deemed compatible with all four considered pillars. On planning for needs and supply, only one quarter of the programs were compatible with the principles of AA, owing to residents in out-of-clinic rotations often being unavailable for extended periods. On regularly adjusting supply to demand, 54% of the programs were compatible. Most (82%) programs' appointment systems were not very compatible with the AA principles, mostly because the proportion of the schedule reserved for urgent appointments was insufficient. Interprofessional collaboration opportunities in the first year of residency allowed 60% of the programs to be compatible with this pillar. CONCLUSIONS: Our study highlights the heterogeneity among local residency programs with respect to their theoretical compatibility with the key principles of AA. Future research to empirically test the hypotheses raised by this study is warranted.