Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A2A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.

Laser-Printed Photoanode: Femtosecond Laser-Induced Crystalline Phase Transformation of WO3 Nanorods for Space-Efficient and Flexible Thin-Film Solar Water-Splitting Cells.

Despite its potential for clean hydrogen harvesting, photoelectrochemical (PEC) water-splitting cells face challenges in commercialization, particularly related its harvesting performance and productivity at an industrial scale. Herein, a facile fabrication method of flexible thin-film photoanode for PEC water-splitting to overcome these limitations, based on laser processing technologies, is proposed. Laser-induced graphene, a carbon structure produced through direct laser writing carbonization (DLWC), plays a dual role: a flexible and stable current collector and a substrate for the hydrothermal synthesis of tungsten trioxide (WO3) nanorods (NRs). To facilitate water-splitting, a femtosecond-pulsed laser (fs laser) is focused on the WO3 NRs, converting their crystalline phase from pristine orthorhombic to monoclinic structure without thermal damage. With NiFe layered double hydroxide (LDH) catalyst, the flexible thin-film photoanode exhibits good PEC performance (1.46 mA cm-2 at 1.23 VRHE) and retains ≈90% of its performance after 3000 bending cycles. With its excellent mechanical properties, the flexible photoanode can be operated in various shapes with different curvatures, enabling space-efficient PEC water-splitting by loading larger photoanode within a given space. This study is expected to contribute to the advancement of large-scale solar water-splitting cells, introducing a new approach to enhance H2/O2 production and expand its application range.

Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure.

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1-5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1-20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1-10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11-20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.

Development and application of a physiologically based pharmacokinetic model for entrectinib in rats and scale-up to humans: Route-dependent gut wall metabolism.

Entrectinib (Rozlytrek®) is an oral antineoplastic agent approved by the U.S. Food and Drug Administration in 2019 for the treatment of c-ros oncogene 1 (ROS1)-positive non-small cell lung cancer and neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors. Although there have been a few studies on the pharmacokinetics of entrectinib, the relative contributions of several kinetic factors determining the oral bioavailability and systemic exposure of entrectinib are still worthy of investigation. Experimental data on the intestinal absorption and disposition of entrectinib in rats were acquired from studies on in vitro protein binding/tissue S9 metabolism, in situ intestinal perfusion, and in vivo dose-escalation/hepatic extraction. Using these datasets, an in-house whole-body physiologically based pharmacokinetic (PBPK) model incorporating the QGut model concepts and segregated blood flow in the gut was constructed and optimized with respect to drug-specific parameters. The established rat PBPK model was further extrapolated to humans through relevant physiological scale-up and parameter optimization processes. The optimized rat and human PBPK models adequately captured the impact of route-dependent gut metabolism on the systemic exposure to entrectinib and closely mirrored various preclinical and clinical observations. Our proposed PBPK model could be useful in optimizing dosage regimens and predicting drug interaction potential in various clinical conditions, after partial modification and validation.

Investigation of the Factors Responsible for the Poor Oral Bioavailability of Acacetin in Rats: Physicochemical and Biopharmaceutical Aspects.

Acacetin, an important ingredient of acacia honey and a component of several medicinal plants, exhibits therapeutic effects such as antioxidative, anticancer, anti-inflammatory, and anti-plasmodial activities. However, to date, studies reporting a systematic investigation of the in vivo fate of orally administered acacetin are limited. Moreover, the in vitro physicochemical and biopharmaceutical properties of acacetin in the gastrointestinal (GI) tract and their pharmacokinetic impacts remain unclear. Therefore, in this study, we aimed to systematically investigate the oral absorption and disposition of acacetin using relevant rat models. Acacetin exhibited poor solubility (≤119 ng/mL) and relatively low stability (27.5-62.0% remaining after 24 h) in pH 7 phosphate buffer and simulated GI fluids. A major portion (97.1%) of the initially injected acacetin dose remained unabsorbed in the jejunal segments, and the oral bioavailability of acacetin was very low at 2.34%. The systemic metabolism of acacetin occurred ubiquitously in various tissues (particularly in the liver, where it occurred most extensively), resulting in very high total plasma clearance of 199 ± 36 mL/min/kg. Collectively, the poor oral bioavailability of acacetin could be attributed mainly to its poor solubility and low GI luminal stability.

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole.

Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6ß-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT.