Molecular Diversity最新文献

Selective recognition of SO₄^2- from HPO₄^2--containing environments is highly challenging, as SO₄^2- and HPO₄^2- not only share similar structures and sizes, but also exhibit similarities in many characteristics such as charge density, acidity, and hydration energy. In this contribution, a post-modifiable trapezoidal cage (1a) was developed to address the selective recognition of SO₄^2- from HPO₄^2-, as well as to cope with the difficulties of trapezoidal cages in post-modification and property variation. Coupled with the newly explored [4 + 4] cyclization strategy, the synthesis efficiency of producing trapezoidal cages has also been greatly improved. Afterward, by taking advantage of the tetrahedrally deployed binding sites of the trapezoidal cage 1a, selective recognition of SO₄^2- from HPO₄^2- can be realized even in complex environments containing many other anions. Through NMR, fluorescence, nonlinear fitting analysis, and HRMS experiments, the binding affinity and binding stoichiometry of 1a + anion were extensively studied. The results demonstrate that 1a + SO₄^2- follows a 1:1 host-guest binding mode and exhibits a much higher binding affinity (K ~ 1.7 × 10⁸ M^-1) than HPO₄^2- (K = 2.6 × 10⁶ M^-1) or any other anions (K = 10⁴-10⁵ M^-1) in 5% methanol/chloroform. The selective recognition of SO₄^2- in complex environments including HPO₄^2- can provide valuable considerations for the precise design of receptors that can distinguish subtle structural differences in substrates, while the post-modification strategy may also help improve the synthesis and extendibility of other covalent cages.

Renin, an aspartyl protease enzyme, is a crucial part of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. However, numerous renin inhibitors, including Aliskiren, Zankiren, Enalkiren, Fasidotril, and Remikiren, are in the clinical arena of managing hypertension, but they are associated with numerous drawbacks. The important one includes modest efficacy in contrast to other antihypertensive agents, which reduces their use as monotherapy; secondly, the related side effects, including hyperkalemia and renal impairment. Thus, considering the unmet need to identify new renin inhibitors, we applied the drug repurposing technique on an 1880 US FDA-approved small molecules database. The research was achieved by performing the structure-based virtual screening (SBVD) on FDA-approved drugs, which was well supported by molecular docking, dynamics, and mechanics studies. This work identified Panobinostat as a possible lead renin inhibitor. The in vitro Elisa-based assay revealed Panobinostat has the potential to inhibit the renin enzyme at the half-maximal concentration (IC₅₀) of 201.27 nM, while standard renin inhibitor Aliskiren portrayed an IC₅₀ of 162.22 nM. The comparable potency to clinical renin inhibitors presents this HDAC inhibitor as a dual-functioning ligand. The findings are significant and well correlated with the plethora of evidence suggesting the role of HDACs in regulating RAAS and cardiovascular functions via the post-translational level modulation of chromatins' structures and functions.

Salicylic acid (SA) functions as a critical phytohormone coordinating developmental regulation and defense responses in plants. Understanding SA's regulatory roles in both homeostasis and stress adaptation necessitates advanced monitoring platforms. We designed six rhodamine probes (R1-R6) containing spirolactam or spirohydrazone bridges to systematically evaluate five-membered spiro structures for SA detection. Furthermore, through Fourier infrared experiments (FTIR) and density functional theory (DFT) calculations, we performed molecular orbital analysis to disclose the SA-responsive mechanism underlying the rhodamine ring-opening process induced by SA. Comparative analysis revealed that spirohydrazone-modified probes displayed enhanced fluorescence performance and improved molecular recognition specificity for SA. The optimized probe R2, incorporating a quinoline moiety, achieved exceptional sensing performance through synergistic hydrogen bonding and C-H…π interactions, demonstrating high selectivity, rapid response kinetics (< 30 s), and excellent sensitivity (LOD = 0.87 μM). Overall, this study successfully visualized endogenous SA distribution in living tomato root systems, establishing a novel design framework for acylhydrazone-based rhodamine sensors and elucidating the SA response mechanism through molecular dynamics simulations.

Ferulic acid, a natural active ingredient, mainly exerts antitumor activity by disrupting mitochondrial function and has the advantages of low toxicity and high efficiency. However, poor water solubility and low bioavailability have limited its further development. This article uses triphenylphosphonium salts (TPP⁺) with both amphiphilicity and tumor mitochondrial targeting to modify the structure of ferulic acid, and designs and synthesizes a series of TPP⁺ conjugated ferulic acid derivatives. Compared with ferulic acid, the water solubility, mitochondrial targeting and antitumor activity of TPP-conjugated ferulic acid derivatives were significantly enhanced. Among them, compound I₄ showed excellent anti-cervical cancer activity, mainly by reducing ATP synthesis and promoting ROS production, thus activating mitochondria-mediated apoptotic signaling to induce apoptosis in HeLa cells. I₄ also inhibited HeLa cell migration and caused cell cycle arrest to the G0/G1 phase. In the mouse model, the effective therapeutic concentration of I₄ was 2.5 mg/kg and the LD₅₀ was 98.11 mg/kg. I₄ demonstrated similar anti-cervical cancer activity, a larger therapeutic window and a higher safety profile than with the first-line anticancer agent cisplatin.

The Arenaviridae family of viruses includes the Machupo virus (MACV), which is associated with the potentially fatal Bolivian hemorrhagic fever, a disease with a mortality rate of 15%-30% depending on the speed of diagnosis and the availability of health facilities. To date, there is no licensed vaccine available for MACV, highlighting the need for a preventive measure. In this work, we use immunoinformatics approaches to create a multi-epitope vaccine based on the most dominant MACV proteins. For constructational epitopes, we selected glycoprotein precurssor (GP), nucleoprotein (NP), RNA-dependant RNA polymerase (L), and Zinc-binding RING finger protein (Z) from garner the proteins essential for replicating and invading a host cell. Using in silico prediction methods, a total of thirteen T-cell epitopes (seven MHC class I and six MHC class II binders) and eight B-cell epitopes were identified as having the greatest potential to elicit strong and broad-spectrum immune responses. These selected epitopes were validated in silico to ensure the highest degree of immunogenicity and no allergenic or toxic effects. To increase the potential of the vaccine to elicit an immune response, the 50S ribosomal protein L7/L12 was added as an adjuvant. The analysis of population coverage indicated that the epitopes could provide immunological protection to nearly 98.04% of the world population. The theoretical vaccine design included 3D modeling and simulation of docking to immunoreceptors like Toll-like receptor 4 (TLR4) and MHC molecules, which confirmed their stable and high-affinity binding interactions. The results from in silico simulations of the immune response also showed abundant production of antibodies and strong engagement of various T-cell subsets. In summary, this study proposes a multi-epitope Machupo virus vaccine candidate that can be tested in the lab to evaluate its effectiveness as a preventative measure for Bolivian hemorrhagic fever.

Wnt/β-catenin signaling pathway plays a major role in the regulation of bone homeostasis. Sclerostin exhibits a high-affinity binding to the Wnt co-receptors LRP5/6 and therefore acts as an extracellular inhibitor of canonical Wnt signaling. Disruption of the interaction between LRP5/6 and sclerostin is essential for Wnt-related metabolic processes that can affect bone health. Consequently, we targeted the loop 2 region of sclerostin, which binds stably to LRP5/6, and employed a series of in silico approaches, including molecular docking and molecular dynamics simulations, to screen drug-like compounds from the DrugBank database. The loop 2 region of sclerostin is relatively flexible and mobile in solution. To enhance the accuracy of screening, we generated eight distinct conformers of sclerostin following initial molecular dynamics simulations. Subsequently, we applied virtual screening methods, including high-throughput virtual screening, standard precision, extra precision, and molecular mechanics generalized Born surface area calculations for each conformer. After merging hits, 50 compounds were further studied with molecular dynamics simulations and binding energy computations over the trajectories. Our results revealed that the compounds DB02675, DB15238, DB04226, DB03325, and DB05644 exhibit inhibitory activity on the loop 2 region of sclerostin.

Biomedical imaging has become an essential tool in the field of early cancer diagnosis and treatment. It is of great significance to develop a method that can monitor tumor hypoxia in real time and maintain a good photodynamic therapy (PDT) effect under hypoxic conditions. To achieve this goal, here we designed and synthesized a novel water-soluble porphyrin derivative, PtTSPP. The photophysical properties of PtTSPP were comprehensively characterized by UV-Vis absorption spectroscopy and fluorescence emission. This porphyrin has an extremely large Stokes shift and red emission (λ_em = 690 nm), which can effectively reduce the interference of background fluorescence and is used for the fluorescence imaging of HeLa cells. PtTSPP has good water solubility, is not prone to aggregation, and has a high singlet oxygen quantum yield. It also exhibits low dark toxicity and excellent photocytotoxicity. These properties make PtTSPP a promising candidate reagent for biomedical imaging and photodynamic therapy.

Multicomponent reactions (MCRs) are one-pot processes in which at least three reactants are combined to assemble a novel target product by intrinsic molecular diversity, optimal atom economy, and high efficiency. The development and design of new MCRs that yield valuable chemical products represent a major focus in organic chemistry. Meldrum's acid is a distinctive β-keto ester that is crucial in organic synthesis, especially in MCRs. The C5 position of this molecule demonstrates significant reactivity towards electrophilic substitution, whereas the carbonyl centers at C4 and C6 are notably vulnerable to nucleophilic attack. Its dual characteristics as both a nucleophile and electrophile, along with its tendency for enolization and decarboxylation, render it an essential synthon for the effective assembly of various heterocyclic scaffolds and acyclic organic compounds. In parallel, isocyanides have attracted significant attention as a versatile building block in MCRs because of their unique ambident reactivity. The combination of Meldrum's acid with isocyanide has opened a powerful avenue in diversity-oriented synthesis, leading to the discovery of unexpected products such as succinimide, carboxamide, imino-furopyranones, cyclopenta[b] pyridines, benzodiazepines, benzooxazepines, amidodiesters, functionalized triamides, and enamides. In continuation of our earlier review on Meldrum's acid and isocyanide-based MCRs, this minireview covers an in-depth discussion of this field, especially focusing on the most recent results from 2015 to 2025.