Editorial

peer reviewedEditorial for the special issue on biobased flow chemistr

User friendly and flexible Kiliani reaction on ketoses using microreaction technology

The Kiliani reaction, i.e. the elongation of the carbon chain by means of cyanide addition to the carbonyl group of carbohydrate derivatives, is studied on lower C3-, C4- and C6-ketoses under continuous flow conditions. Depending on the process parameters, the corresponding cyanohydrins or alpha-hydroxycarboxylic acids are obtained. A simple on-line purification of the effluent is studied using cation exchange resins. Reactions provide high yields and selectivity within short residence times, emphasizing the assets of the continuous flow process versus the batch process

A perspective on the synthetic potential of biobased building blocks for heterocyclic chemistry

peer reviewedHeterocycles are a wide occurrence in molecules with a variety of applications: from the pharmaceutical industry to polymers, cosmetics, food additives and dyes. However, most of their synthetic pathways are based on finite petrobased building blocks. This chapter discusses different renewable feedstock sources, their prominence and compo- sition as well as the challenges faced regarding their transformation into valuable primary building blocks. Following this, a brief overview of secondary building blocks Advances in Heterocyclic Chemistry Copyright # 2024 Elsevier Inc. ISSN 0065-2725 All rights are reserved, including those 1 https://doi.org/10.1016/bs.aihch.2024.04.003 for text and data mining, AI training, and similar technologies. 2 Loïc Bovy and Jean-Christophe M. Monbaliu is discussed before providing examples of their incorporation in (un)fused heterocycles with an emphasis on compounds with known applications. Building upon these separate topics, perspectives aiming at solving the encountered and discussed issues are provided

Intensified Continuous Flow Process for the Scalable Production of Bio-Based Glycerol Carbonate.

peer reviewedA subtle combination of fundamental and applied organic chemistry toward process intensification is demonstrated for the large-scale production of bio-based glycerol carbonate under flow conditions. The direct carbonation of bio-based glycidol with CO2 is successfully carried out under intensified flow conditions, with Barton's base as a potent homogeneous organocatalyst. Process metrics for the CO2 coupling step (for the upstream production, output: 3.6 kg day-1, Space Time Yield (STY): 2.7 kg h-1 L-1, Environmental factor (E-factor): 4.7) outclass previous reports. High conversion and selectivity are achieved in less than 30 s of residence time at pilot scale with a stoichiometric amount of CO2. Supporting DFT computations reveal the unique features of the mechanism in presence of Brønsted bases

Radical c–h18f-difluoromethylation of heteroarenes with [18f]difluoromethyl heteroaryl-sulfones by visible light photoredox catalysis

peer reviewedThe18F-labeling of CF2H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope18F for positron emission tomography (PET). Following up on the reported efficiency of the [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1) as a18F-difluoromethylating reagent, we investigated the influence of structurally-related [18F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C–H18F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [18F]difluoromethyl heteroaryl-sulfones [18F]5a–[18F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([18F]5a, [18F]5c, and [18F]5f) were selected for the fully automated radiosynthesis on a FASTlab™ synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as 18 F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [18F]1 influenced the amount of fac-IrIII(ppy)3 and the residence time needed to ensure a complete C– H18F-difluoromethylation process. The photocatalytic C–H18F-difluoromethylation reaction with the reagents [18F]5a, [18F]5c, and [18F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C–H 18 F-difluoromethylation process

Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans

Objectives: The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans. Methods: Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The ke of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h−1. Ka and Vd parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests. Results: In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of ke across different genotypes. Conclusions: The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data

New insights into the role of<i> VKORC1</i> polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

[EN] Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharma-codynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3-and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.This research was financially sponsored in part by NASA grant #80 NSSC19M0148 from the EPSCoR program, and by grant #1R16 GM149372 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) . The content of this manuscript does not represent the views of the National Institutes of Health, NASA or the United States Government. No funded writing assistance was utilized in the production of this manuscript.Rodríguez-Fernández, K.; Reynaldo-Fernández, G.; Reyes-González, S.; De Las Barreras, C.; Rodríguez-Vera, L.; Vlaar, C.; Monbaliu, JM.... (2024). New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model. Biomedicine & Pharmacotherapy. 170. https://doi.org/10.1016/j.biopha.2023.11597717