RESUMEN
Herein, a novel and facile organic photosensitizer (thioxanthone)-mediated energy-transfer-enabled (EnT-enabled) dearomative [2+2] cycloaddition of aromatic heterocycles/maleimides for green synthesis of cyclobutane-fused polycyclic skeletons is reported. Mechanistic investigations revealed that different EnT pathways by triplet thioxanthone were initiated when different aromatic heterocycles participated in the reaction, giving the corresponding excited intermediates, which underwent the subsequent intermolecular [2+2] cycloaddition to access the desired highly functionalized cyclobutane-fused polycyclic skeletons.
RESUMEN
Acyl radicals have been generated from the decarboxylation of α-oxocarboxylic acids by using a readily accessible organic pyrimidopteridine photoredox catalyst under ultraviolet-A (UV-A) light irradiation. These reactive acyl radicals were smoothly added to olefins such as styrenes and diverse Michael acceptors, with the assistance of H2O/D2O as hydrogen donors, enabling easy access to a diverse range of ketones/ß-deuterio ketones. A wide range of α-oxocarboxylic acids are compatible with this reaction, which shows a reliable, atom-economical, and eco-friendly protocol. Furthermore, postsynthetic diversifications and applications are presented.
RESUMEN
Importance: BRAF variants are associated with tumor progression; however, the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma (ICC) are largely unknown. Objective: To explore the association of BRAF variant subtypes with disease characteristics, prognosis, and targeted therapy response in patients with ICC. Design, Setting, and Participants: In this cohort study, 1175 patients who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital in China. Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify BRAF variants. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using Cox proportional hazards regression. Associations between BRAF variants and targeted therapy response were tested in 6 BRAF-variant, patient-derived organoid lines and in 3 of the patient donors of those lines. Data were analyzed from June 1, 2021, to March 15, 2022. Interventions: Hepatectomy in patients with ICC. Main Outcomes and Measures: The association of BRAF variant subtypes with OS and DFS. Results: Of 1175 patients with ICC, the mean (SD) age was 59.4 (10.4) years and 701 (59.7%) were men. A total of 20 different subtypes of BRAF somatic variance affecting 49 patients (4.2%) were identified; V600E was the most frequent allele in this cohort, accounting for 27% of the identified BRAF variants, followed by K601E (14%), D594G (12%), and N581S (6%). Compared with patients with non-V600E BRAF variants, patients with BRAF V600E variants were more likely to have large tumor size (10 of 13 [77%] vs 12 of 36 [33%]; P = .007), multiple tumors (7 of 13 [54%] vs 8 of 36 [22%]; P = .04), and more vascular/bile duct invasion (7 of 13 [54%] vs 8 of 36 [22%]; P = .04). Multivariate analysis revealed that BRAF V600E variants, but not overall BRAF variants or non-V600E BRAF variants, were associated with poor OS (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; P = .03) and DFS (HR, 1.66; 95% CI, 1.03-2.97; P = .04). There were also broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Conclusions and Relevance: The findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Identifying and classifying BRAF variants may be able to help guide precise treatment for patients with ICC.
