Latest ArticlesNine new fluorine-containing drugs have been approved by the US Food and Drug Administration (FDA) in 2021, which are presented in this review article. These small molecular drugs feature aromatic fluorine, trifluoromethyl and chlorodifluoro groups. The therapeutic areas of these fluorine-containing drugs include multiple myeloma, lymphoma, HIV, chronic heart failure, chronic myeloid leukemia, (ANCA)-associated vasculitis, migraines, von Hippel-Lindau disease, and non-small cell lung cancer. The brief biological activities and the synthetic methods have been discussed in this review for each of these nine drugs.
Allenylboronates represent a very intriguing class of organoborons but are challenging to synthesis. In addition, these compounds are typically unstable, rendering the separation difficult. We report herein a practical and concise route to a new class of stable, easy-separable allenyl B(MIDA) via a hydrazination/fragmentation of B(MIDA)-propargylic alcohols. The synthesis of optically active allenyl B(MIDA) was also achieved. Interesting reactivity of the resulting product was observed.
Three-residue cyclophane-forming enzymes (3-CyFEs) are a group of radical S-adenosylmethionine (SAM) enzymes involved in the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). 3-CyFE catalyzes the crosslinking between an aromatic residue (Ω1) and a non-aromatic residue (X3) in a Ω1-X2-X3 motif to produce a cyclophane ring, a key step in the biosynthesis of the RiPP natural product triceptide. In this study, we perform a genome-wide search for the Xye-type triceptides, showing these RiPPs are likely class-specific and only present in gamma-proteobacteria. The 3-CyFE PauB from Photorhabdus australis exhibits a relaxed substrate specificity on the X3 position, but glycine in this position is not suitable for cyclophane formation. We also reconstituted the activity of PauB in vitro, showing it produces the N-terminal cyclophane firstly, and then the C-terminal ring, whereas the middle cyclophane is produced in the last step.
Plaque plays a central role in atherosclerosis (AS) progression, whereas inflammation and destruction of the plaque microenvironment contribute to plaque advancement. As a result, a therapy regime, which combines anti-inflammation and inhibition-degradation of plaque matrix, appears to be a promising strategy to combat AS. Herein, we report a pH-sensitive liposome co-loading with the anti-inflammatory agent (oridonin, ORD) and plaque-collagen protector (marimastat) for anti-AS therapy. ORD was first conjugated with hyaluronic acid (HA) to target the inflammation contributor, pro-inflammatory macrophages. Then, the conjugate assembled onto the MATT-loaded liposomes. The co-loaded system (~150 nm) significantly improved pharmacokinetics over the liposomes without anchoring the conjugate and accumulated effectively in the plaque. The preparation administration allowed efficient anti-AS activities in high-fat diet (HFD)-Apoe-/- mice by decreasing the pro-inflammatory cytokine expression in the serum, lessening the lesion area, alleviating the plaque collagen degradation, promoting macrophage polarization from phenotypic M1 to M2, reducing T helper (Th) 17 cells (Th17)/T regulatory cells (Tregs) and Th1/Th2 ratio, etc. Furthermore, the serum determination in AS patients demonstrated high expression of the inflammatory cytokines, indicating our finding may offer a potential guideline for clinical practice.
O-Acyl ketoximes has been proven to be versatile building blocks for practical construction of N-heterocycles. In the last few years, diverse catalytic systems have been discovered to enable efficient transformations of O-acyl ketoximes to a range of nitrogen-heterocycles. Herein, we summarized our recent examples of novel nitrogen-heterocycle formation with new function findings of O-acyl ketoximes through facile aerobic copper catalysis, metal-free NO bond activation, multi-component assembly, and bis-annulations. From the green chemistry perspective, these works represent efficient methods with high atom economy, high selectivity, and minimized chemical waste. These findings also complement well to the previous mainly copper-based catalytic systems and more importantly enrich the oxime chemistry in organic synthesis.
Gambogic acid (GA) is a potential clinical anticancer drug that can exert antitumor effects via various molecular mechanisms. Notwithstanding, GA's low water solubility, poor stability, short half-life, and unavoidable toxic side effects have significantly hampered its clinical application. Erythrocyte membrane-coated nanoparticles (RBCM-NPs) improve drug's physicochemical properties, biocompatibility, and pharmacokinetic behaviors, allowing for long-term drug circulation and passive targeting. In this study, a novel biomimetic drug delivery system (DDS) against hepatocellular carcinoma was prepared by covering RBCM on GPP-NPs (GA-loaded mPEG-PLA NPs) to develop the RBC@GPP-NPs. In comparison to RBCM-free nanoparticles and free GA, RBC@GPP-NPs improved the drug's water solubility, stability, safety, and anti-tumor activity in vivo. We expect that this bionic nanoparticle composite can expand the clinical applicability of GA and provide a feasible solution for the research and development of GA's nano-formulation.
The fabrication of highly effective photosensitizers has received considerable attention because of their attractive functions and applications in the fields of photodynamic therapy, photosynthesis, photocatalysis, etc. Thus, it is highly desirable to develop a new approach to enhance photosensitization efficiency. Herein, through coordination-driven self-assembly, a series of metallacycles with efficient fluorescence resonance energy transfer (FRET) were effectively constructed, which displayed higher photosensitization efficiency and photocatalytic activity than their model metallacycles without FRET due to broadband absorption and singlet energy transfer from the energy acceptor to the energy donor. Moreover, iodization of fluorophores induced a significant enhancement of the photosensitization efficiency and photocatalytic activity of the metallacycles. This research provides an efficient strategy for improving photosensitization efficiency and a promising platform for the preparation of effective photosensitizers and photocatalysts.
An N-heterocyclic carbene (NHC)-catalyzed carbonyl nucleophilic substitution reaction between 1-cyclopropylcarbaldehydes and N-sulfonyl imines is developed for access to linear β-aminoenone products. The β-aminoenones containing cyclopropyl fragments can be afforded in moderate to excellent yields under mild conditions. The reaction features excellent trans-diastereoselectivities and the desired aminoenone products are all afforded as Z-isomers.
Silkworm pupa protein (SPP) that obtained by traditional method usually had a high fat content, which would impose restrictions on the further use of SPP. Herein, various functionalized ionic liquids (ILs) were used to extract SPP from silkworm pupae, the structure-performance relationship of ILs with their SPP separation performance were explored at the same time. The research showed that the maximum extraction yield of SPP was up to 62.6% with less than 0.5% low fat content by using 1-ethyl-3-methylimidazolium chloride ([Emim]Cl), when the dissolution experiment was conducted at 90 ℃ for 24 h with ethanol bath as the regeneration solvent. Comparing with the structure of raw material, the regenerated SPP maintained the native protein backbone. Meanwhile, all regenerated SPP showed a decreased crystallinity, which also exhibited decreased fraction of the α-helix comparing to that β-sheet united with coil random structures.
Inhibition of foam cell formation is considered a promising treatment method for atherosclerosis, the leading cause of cardiovascular diseases worldwide. However, currently available therapeutic strategies have shown unsatisfactory clinical outcomes. Thus, herein, we design aloperine (ALO)-loaded and hyaluronic acid (HA)-modified palladium (Pd) octahedral nanozymes (Pd@HA/ALO) that can synergistically scavenge reactive oxygen species (ROS) and downregulate cyclooxygenase-2 (COX-2) expression to induce macrophage polarization, thus inhibiting foam cell formation to attenuate atherosclerosis. Due to the targeted effect of HA on stabilin-2 and CD44, which are overexpressed in atherosclerotic plaques, Pd@HA/ALO can actively accumulate in atherosclerotic plaques. Subsequently, the antioxidative effects of Pd octahedral nanozymes are mediated by their intrinsic superoxide dismutase- and catalase-like activities capable of effective scavenging of ROS. In addition, anti-inflammatory effects are mediated by controlled, on-demand near-infrared-triggered ALO release leading to inhibition of COX-2 expression. Importantly, the combined therapy can promote the polarization of macrophages to the M2 subtype by upregulating Arg-1 and CD206 expression and downregulating expression of TNF-α, IL-1β and IL-6, thereby inhibiting atherosclerosis-related foam cell formation. In conclusion, the presented in vitro and in vivo data demonstrate that Pd@HA/ALO enhanced macrophage polarization to reduce plaque formation, identifying an attractive treatment strategy for cardiovascular disease.
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