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Herein, we present a comprehensive total synthesis of cannabidiol integrating both batch and continuous flow conditions. Our approach is planned to streamline the synthesis of olivetolic acid derivatives and utilize an enantiomerically pure monoterpene moiety obtained from naturally occurring (R)-(+)-limonene by photocatalysis. Key reactions, including the synthesis of olivetolic ester and a Friedel-Crafts alkylation, are successfully adapted to continuous flow, resulting in improved yields and selectivities. This study not only offers a scalable and efficient route for cannabidiol synthesis but also contributes to the synthetic approaches to access cannabinoids (diversity synthesis), with potential applications in medicinal and industrial contexts., (© 2024 Wiley-VCH GmbH.)

The integration of multicomponent reactions (MCRs), which offer a rapid and efficient approach to synthesize complex molecular scaffolds, with continuous flow platforms is an increasingly recognized strategy in green synthesis. This association enables precise control over reaction parameters, including improved kinetics and selectivity, reduced reaction times, enhanced yields and scalabilities, while aligning with sustainable and green chemistry principles through resource utilization, minimized waste, and reduced environmental impact. This review presents a critical analysis of recent studies covering the MCR-continuous flow association, with a focus on achieving greener and more sustainable synthesis practices., (© 2024 Wiley-VCH GmbH.)

Background: The combination of photodynamic therapy (PDT) and LL-37 has never been tested in an animal study and our research team background suggests this strategy might be a promising alternative to intensify periodontitis resolution. This study aimed to assess the effects of multiple sessions of PDT with chlorin-e6 conjugated to the antimicrobial peptide LL-37 loaded nanoemulsion, as adjunctive therapy in experimental periodontitis in rats., Methods: Experimental periodontitis was induced in 81 rats. After disease establishment, animals were assigned to three groups: SRP (scaling and root planning); SRP + 1PDT, SRP followed by a single PDT session; SRP + 4PDT (n = 27), SRP followed by four PDT sessions at 0, 24, 48 and 72 h after SRP. Animals were subjected to euthanasia at 7, 14 and 28 days, and samples were submitted to osteoclast quantification, immunological and microtomography analysis., Results: All treatments resulted in significant periodontal improvements and there was no significant difference between the groups in both local inflammatory response and healing process. Minimal adjunctive effects could be found for the combined therapy in terms of cytokine levels (IL-1β and IL-10), with no statistical significance. However, the number of TRAP-positive osteoclasts per mm of alveolar bone linear surface for the group treated with PDT sessions was significantly lower than those treated with SRP only., Conclusions: Multiple PDT sessions with chlorin-e6 and LL-37 nanoemulsion as an adjunct to scaling and root planning reduced the presence of osteoclast in the local site but did not contribute towards bone regeneration and IL-1β and IL-10 levels., Competing Interests: Declaration of competing interest This manuscript has been read and approved in final form by all authors and the authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Curcumin serves as a photosensitizer (PS) in the context of microbial inactivation when subjected to light exposure, to produce reactive oxygen species, which exhibit efficacy in eradicating microorganisms. This remarkable property underscores the growing potential of antimicrobial photodynamic therapy (aPDT) in the ongoing fight against bacterial infections. Considering this, we investigate the efficacy of various in vitro curcumin formulations within a PDT protocol designed to target Staphylococcus aureus. Specifically, we conduct a comparative analysis involving synthetic curcumin (Cur-Syn) and curcumin derivatives modified with chlorine (Cl), selenium (Se), and iodine (I) (Cur-Cl, Cur-Se, Cur-I). To assess the impact of aPDT, we subject S. aureus to incubation with curcumin, followed by irradiation at 450 nm with energy doses of 3.75, 7.5, and 15 J/cm 2 . Our investigation encompasses an evaluation of PS uptake and photobleaching across the various curcumin variants. Notably, all three modifications (Cur-Cl, Cur-Se, Cur-I) induce a significant reduction in bacterial viability, approximately achieving a 3-log reduction. Interestingly, the uptake kinetics of Cur-Syn and Cur-Se exhibit similarities, reaching saturation after 20 min. Our findings suggest that modifications to curcumin have a discernible impact on the photodynamic properties of the PS molecule., (© 2024 American Society for Photobiology.)

Palladium(II) complexes have stimulated research interest mainly due to their in vitro cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh 3 ) 2 ]PF 6 (A1), [Pd(cur)(dppe)]PF 6 (A2), [Pd(cur)(dppp)]PF 6 (A3), [Pd(cur)(dppb)]PF 6 (A4) and [Pd(cur)(dppf)]PF 6 (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR ( 1 H, 13 C, 31 P{ 1 H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The in vitro cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC 50 values than free curcumin and the precursors [PdCl 2 (P-P)]. IC 50 results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC 50 values, around 5 μmol L -1 , and the complexes appeared to be more active (lower IC 50 values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.

Herein, we present an overview of continuous flow chemistry, including photoflow and electroflow technologies in the preparation of active pharmaceutical ingredients (APIs) and fine chemical intermediates. Examples highlighting the benefits and challenges associated with continuous flow processes, mainly involving continuous thermal, photo- and electrochemical transformations, are drawn from the relevant literature, especially our experience and collaborations in this area, with emphasis on the synthesis and prospective scale-up.