Enhanced Oral Bioavailability of Rivaroxaban-Loaded Microspheres by Optimizing the Polymer and Surfactant Based on Molecular Interaction Mechanisms.

This study aimed to develop microspheres using water-soluble carriers and surfactants to improve the solubility, dissolution, and oral bioavailability of rivaroxaban (RXB). RXB-loaded microspheres with optimal carrier (poly(vinylpyrrolidone) K30, PVP) and surfactant (sodium lauryl sulfate (SLS)) ratios were prepared. 1H NMR and Fourier transform infrared (FTIR) analyses showed that drug-excipient and excipient-excipient interactions affected RXB solubility, dissolution, and oral absorption. Therefore, molecular interactions between RXB, PVP, and SLS played an important role in improving RXB solubility, dissolution, and oral bioavailability. Formulations IV and VIII, containing optimized RXB/PVP/SLS ratios (1:0.25:2 and 1:1:2, w/w/w), had significantly improved solubility by approximately 160- and 86-fold, respectively, compared to RXB powder, with the final dissolution rates improved by approximately 4.5- and 3.4-fold, respectively, compared to those of RXB powder at 120 min. Moreover, the oral bioavailability of RXB was improved by 2.4- and 1.7-fold, respectively, compared to that of RXB powder. Formulation IV showed the highest improvement in oral bioavailability compared to RXB powder (AUC, 2400.8 ± 237.1 vs 1002.0 ± 82.3 h·ng/mL). Finally, the microspheres developed in this study successfully improved the solubility, dissolution rate, and bioavailability of RXB, suggesting that formulation optimization with the optimal drug-to-excipient ratio can lead to successful formulation development.

Elimination of A-234 from the environment: Effect of different decontaminants.

With the fact that there are Novichoks in the list of toxic chemicals by the Chemical Weapons Convention parties, it is necessary to develop methods of effective neutralization of the agents as well as for other organophosphorus toxic substances. However, experimental studies on their persistence in the environment and effective decontamination measures remain scarce. Therefore, here, we investigated the persistence behavior and decontamination methods of A-234 (ethyl N-[1-(diethylamino)ethylidene]phosphoramidofluoridate), a Novichok series, A-type nerve agent to assess its potential risk to the environment. Different analytical methods were implemented, including 31P solid-state magic angle spinning nuclear magnetic resonance (NMR), liquid 31P NMR, gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry, and vapor-emission screening using a microchamber/thermal extractor with GC-MS. Our results showed that A-234 is extremely stable in sand and poses a long-lasting risk to the environment even when released in trace quantities. Moreover, the agent is not easily decomposed by water, dichloroisocyanuric acid sodium salt, sodium persulfate, and chlorine-based water-soluble decontaminants. However, it is efficiently decontaminated by Oxone® monopersulfate, calcium hypochlorite, KOH, NaOH, and HCl within 30 min. Our findings provide valuable insights for eliminating the highly dangerous Novichok agents from the environment.

Synthesis of Cyclic N-Acyl Amidines by [3 + 2] Cycloaddition of N-Silyl Enamines and Activated Acyl Azides.

In this study, we describe the synthesis of cyclic N-acyl amidines from readily available N-heteroarenes. The synthetic methodology utilized the versatile N-silyl enamine intermediates from the hydrosilylation of N-heteroarenes for the [3 + 2] cycloaddition reaction step. We evaluated various acyl azides and selected an electronically activated acyl azide, thereby achieving a reasonable yield of cyclic N-acyl amidines. We analyzed the relationship between the reactivity of each step and the electronic nature of substrates using in situ nuclear magnetic resonance spectroscopy. In addition, we demonstrated gram-scale synthesis using the proposed methodology.

(3 + 2) Cycloaddition Reaction of the Endocyclic N-Silyl Enamine and N,N'-Cyclic Azomethine Imine.

We describe the (3 + 2) cycloaddition reaction of endocyclic N-silyl enamines and N,N'-cyclic azomethine imines. This process utilized the versatile endocyclic N-silyl enamine intermediates from the dearomative hydrosilylation of N-heteroarenes. The resulting tetracyclic pyrazolidinone structure was synthesized by a straightforward and atom-economical process. We also discussed the plausible origins of the different reactivity and endo/exo selectivity in terms of the structures of each proposed transition state. The successful gram-scale synthesis demonstrated the synthetic utility.

Synthesis of Cyclic Amidines from Quinolines by a Borane-Catalyzed Dearomatization Strategy.

Described herein is the development of a new synthetic route to cyclic amidines from quinolines. The borane-catalyzed 1,4-hydrosilylation of quinoline was utilized for the dearomatization of the quinolines. The dearomatized enamine intermediate was subsequently reacted with a broad range of organic azides to produce the corresponding cyclic amidines (3,4-dihydroquinolinimines) via a [3 + 2] cycloaddition pathway. Preliminary mechanistic studies suggested that the hydride shift was involved during the cycloaddition.

Ni-catalyzed 1,2-benzylboration of 1,2-disubstituted unactivated alkenes.

Nickel-catalyzed 1,2-carboboration of alkenes is emerging as a useful method for chemical synthesis. Prior studies have been limited to only the incorporation of aryl groups. In this manuscript, a method for the 1,2-benzylboration of unactivated alkenes is presented. The reaction combines readily available alkenes, diboron reagents and benzylchlorides to generate synthetically versatile products with control of stereochemistry. The utility of the products as well as the mechanistic details of the process are also presented.

Total Synthesis of (-)-Phorbaketal A.

A convergent asymmetric total synthesis of phorbaketal A was achieved in 10 steps through a Au(I)-catalyzed intramolecular spiroketalization reaction of an alkyne diol intermediate prepared from (R)-carvone and geranial. The spiroketalization reaction was regio- and stereoselective and was accompanied by isomerization of an exo-olefin into the trisubstituted olefin to form a unique spiroketal structure of phorbaketals.

Metal-Free Hydrosilylation Polymerization by Borane Catalyst.

The first example of metal-free hydrosilylation polymerization between dienes and disilanes is developed by using a borane catalyst, B(C6F5)3 to replace precious transition-metal-based systems. Under the easy-to-handle and mild conditions, a step-growth polymerization of two readily available diene and disilane units was achieved with high degrees of polymerization. Various combinations of dienes and disilanes produced polycarbosilanes with a broad range of structures and properties.

Boron-catalyzed silylative reduction of quinolines: selective sp3 C-Si bond formation.

A silylative reduction of quinolines to synthetically versatile tetrahydroquinoline molecules involving the formation of a C(sp(3))-Si bond exclusively ß to nitrogen is described. Triarylborane is a highly efficient catalyst (up to 1000 turnovers), and silanes serve as both a silyl source and a reducing reagent. The present procedure is convenient to perform even on a large scale with excellent stereoselectivity. Mechanistic studies revealed that the formation of a 1,4-addition adduct is rate-limiting while the subsequent C(sp(3))-Si bond-forming step from the 1,4-adduct is facile.

Phorbasones A and B, sesterterpenoids isolated from the marine sponge Phorbas sp. and induction of osteoblast differentiation.

Two new sesterterpenoids, phorbasones A (1) and B (2), were isolated from the Korean marine sponge Phorbas sp. Their complete structures were elucidated by spectral data and chemical reactions. Phorbasone A exhibited a positive effect on the calcium deposition activity in C3H10T1/2 cells. The biogenic origin of the core structure is believed to be through a novel rearrangement from the ansellone carbon structure.

Phorbaketals A, B, and C, sesterterpenoids with a spiroketal of hydrobenzopyran moiety isolated from the marine sponge Phorbas sp.

Three new sesterterpenoids, phorbaketals A (1), B (2), and C (3) which have a spiroketal of the hydrobenzopyran moiety, were isolated from the Korean marine sponge Phorbas sp. Their complete structures were elucidated by spectral and chemical methods. They exhibited moderate cytotoxicity against human colorectal, hepatoma, and lung cancer cell lines. Furthermore, the cultivation of the bacterial fraction from the sponge afforded compound 1.