RSC medicinal chemistry最新文献

SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC₅₀ = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.

Histone deacetylase 8 (HDAC8) is a class I enzyme associated with various diseases, including cancer and neurological disorders. Although small-molecule HDAC inhibitors have been developed, their lack of selectivity often leads to off-target effects and toxicities. Alternatively, targeting specific HDAC isoforms for their degradation represents a more precise therapeutic strategy. This review focuses on the design and development of proteolysis-targeting chimeras (PROTACs) that selectively degrade HDAC8. We explore how existing selective HDAC8 inhibitors can be leveraged as warheads in PROTACs to effectively eliminate the enzyme. Recent studies have successfully designed HDAC8-selective PROTACs by linking HDAC8 inhibitors to E3 ubiquitin ligase recruiters such as VHL and CRBN. These PROTACs have demonstrated high potency in degrading HDAC8 in various cancer cell lines with single-digit nanomolar DC₅₀ values, showing superior anti-proliferative effects compared to their parent inhibitors. Therefore, apart from these handful of reports, more research related to HDAC8-PROTAC should provide a better therapeutic development technology for HDAC8-associated disorders while avoiding any therapy-related adversities and complications.

The identification of novel anti-tubercular agents capable of eliciting lethal responses against drug-resistant tuberculosis is critically needed to address the escalating mortality from tuberculosis. Mycobacterium tuberculosis, the etiological agent of this disease, employs a highly efficient energy-producing machinery, the oxidative phosphorylation pathway. Mycobacterium can withstand extreme environmental conditions due to the robust functionality of this multicomponent pathway, which satisfies its energy requirements, during both the persistent phase under stress and the active growth phase. Considering the significance of this biological pathway, in this review we described the dynamics of oxidative phosphorylation and the rationale for targeting its essential components. Furthermore, we provide a comprehensive overview of literature-reported inhibitors, targeting key elements of this pathway, namely, type II NADH dehydrogenase, cytochrome-bd oxidase, and ATP synthase.

Acute myeloid leukaemia (AML) is a clonal proliferative malignant hematologic disease of hematopoietic stem cells, characterized by the accumulation of immature progenitor cells and the inhibition of hematopoietic function due to blocked differentiation, which is a genetically heterogeneous and dynamic disease and the most common type of leukemia in adults. Studies have shown that methyltransferase-like protein 3 (METTL3) is highly expressed in AML cells, regulating methylation modifications that drive the development of leukemia. This discovery has become a major breakthrough in the treatment of AML, as it is possible to address common issues in current chemotherapy, such as drug resistance, by developing METTL3 inhibitors. This review summarizes the strategies for discovering and optimizing the medicinal chemistry of METTL3 inhibitors, provides a reference for future drug development, and looks forward to the potential application prospects of METTL3 inhibitors in clinical practice.

Prodrug strategies are used to enhance the physicochemical and pharmaceutical properties of drug candidates that may not be suitable for specific delivery or are limited by formulation options. A prodrug derivative is converted into its active pharmaceutical ingredient (drug) through enzymatic or chemical reactions within the body. Antiviral nucleoside prodrugs have garnered considerable interest in drug discovery, leading to the approval of key drugs such as remdesivir (SARS-CoV-2), Sovaldi (hepatitis C virus, HCV), and tenofovir disoproxil fumarate [hepatitis B virus (HBV) and human immunodeficiency viruses (HIV)]. Their success lies in improving the oral bioavailability and delivering the parent drug to the targeted tissues. This review focuses on the prodrugs of antiviral nucleosides evaluated in humans (approved, in development or terminated), providing an overview of the different approaches utilized and discussing their in vitro and in vivo benefits.

Acetylcholinesterase (AChE) plays a pivotal role in Alzheimer's disease by accelerating acetylcholine breakdown, leading to cognitive decline. In this study, a series of novel isoxazolone derivatives were synthesized and structurally characterized using spectroscopic methods. The compounds were evaluated for their AChE inhibitory activity, where several candidates demonstrated stronger inhibition than the standard drug Donepezil. Molecular docking supported these findings, highlighting favorable interactions within the enzyme's active site. Selected compounds also exhibited promising antioxidant properties in the DPPH assay. A developed QSAR model provided insights into structural features contributing to bioactivity. In silico ADMET profiling indicated drug-like behavior, and molecular dynamics simulations confirmed the stability of the top ligand-enzyme complexes. Collectively, the results underscore the potential of isoxazolone-based scaffolds as multifunctional agents for managing Alzheimer's disease. Further biological evaluation is recommended to explore their therapeutic applicability.

Targeted protein degradation (TPD) has emerged as a powerful strategy for eliminating disease-causing proteins. The prolyl isomerase Pin1 is an attractive therapeutic target given its oncogenic function. Here, we develop PIPWF, a novel peptide degrader that induces Pin1 degradation through multivalent binding and conformational destabilization. Pin1 degradation attenuates cancer-associated fibroblast (CAF) activation to reshape the fibrotic tumor microenvironment and enhance chemosensitivity via ENT1-mediated gemcitabine uptake. In vivo results demonstrated that both PIPWF and its nanoformulation M-PIPWF synergized with gemcitabine to induce tumor regression and prolong survival, illustrating a novel peptide-based TPD strategy against Pin1-driven malignancies.

Bolinaquinone (BLQ, 1), a hydroxyquinone sesquiterpene, has been reported to inhibit clathrin mediated endocytosis. As there is no reported clathrin IC₅₀ or commercial source of BLQ, we examined the related marine hydroxysesquiterpenes (5-10) and noted good levels of CME inhibition in a subset of these analogues. Off-target inhibition of dynamin GTPase, another key endocytosis protein, was also noted. Given the potentially complex synthesis of BLQ analogues, density functional theory (DFT) computational analysis of BLQ (1) was applied to determine potential structural modifications that would retain the electronic and conformation requirements of BLQ, but offer a more rapid access to analogue development. This analysis suggested that a minimal pharmacophore comprising substituted naphthoquinones such as 11 met our requirements. Focused library synthesis and biological screening identified naphthoquinone based BLQ analogues with excellent inhibition of the clathrin-amphiphysin protein-protein interaction (NTD-PPI, measured by ELISA) and in cell CME inhibition. Replacement of BLQ's decalin moiety gave two naphthalene-1,4-dione analogues, 2-((3-hydroxyphenyl)amino) 12 and 2-((3-hydroxy-4-methylphenyl)amino) 13, with modest inhibition of the clathrin N-terminal-amphiphysin protein-protein interaction (NTD-PPI), but with off-target inhibition of dynamin. Further modifications yielded 2-chloro-3-((3-hydroxyphenyl)amino) 23, with an NTD-PPI IC₅₀ = 2.77 ± 0.9 μM, with reduced dynamin inhibition. Further modification afforded 2-chloro-3-((4-hydroxyphenyl)amino) 26 and 5-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino) 27 that were dynamin inactive and 19 μM potent clathrin inhibitors (NTD-PPI). Compound 26 retuned excellent inhibition of clathrin mediated endocytosis in U2OS cells (IC₅₀ = 2.2 ± 0.9 μM). Molecular docking and dynamic analysis with BLQ (1) and 23 across the three published clathrin crystal structures was consistent with these analogues preferentially binding within clathrin's site 1. Clathrin plays a role in cell division and quinones are known to be cytotoxic; this was confirmed herein against a broad panel of cancer cell lines. While we do not directly link the cytotoxic effects of these analogues with their clathrin inhibition, this does, as with all small molecule probes, support caution in their use. Ideally small molecule probes spanning multiple chemotypes (e.g. the Pitstop 1 and Pitstop 2 families of clathrin inhibitors) should be used to minimise off target effects and provide compelling information of target specific biological effects.

Ferroptosis is one of the regulated cell death pathways. Molecular mechanisms underlying ferroptosis involve iron-dependent lipid peroxidation, which results in cell-deleterious membrane damage. Ferroptosis-inducing agents have been identified as attractive candidates for anticancer drug development as they can bypass drug resistance in cancer cells. Among pro-ferroptotic agents are many organometallic complexes, including ferrocenyl compounds. In this review, we demonstrate that suitably designed ferrocene-containing molecules can induce ferroptosis in different cancer cell types both in vitro and in vivo. Their pro-ferroptotic activity is triggered by diverse initiating factors through different mechanisms (e.g. redox activation, thermal and light activation, and GPX4 inhibition combined with ROS overproduction). Moreover, ferrocenyl bioconjugates are often cancer-cell-selective and trigger ferroptosis in combination with other regulated cell-death pathways, such as apoptosis and immunogenic cell death. Dual or multimodal anticancer activity mechanisms are sought after in modern anticancer therapy approaches as they help to overcome the problem of drug resistance. Research on ferrocene-based ferroptosis inducers, however, is still in the early stage. Hence, more time and effort are needed to fully elucidate the potential of ferrocenes as ferroptosis initiators in cancer therapy.

Pancreatic cancer remains one of the deadliest malignancies of the 21st century, with a five-year survival rate below 12%. Its growing incidence is strongly linked to modern lifestyles, marked by obesity, diabetes, overnutrition, and physical inactivity. Current chemotherapies offer limited success and are often burdened by severe side effects, highlighting the urgent need for more effective and selective treatments. In response, we have developed a new class of easily synthesized, amphiphilic symmetric diiminoguanidines and evaluated their antiproliferative activity against pancreatic cancer cell lines. Several compounds demonstrated remarkable efficacy and selectivity, positioning them as strong candidates for further in vivo evaluation. Fluorescence microscopy revealed that these molecules rapidly localize into mitochondria. Preliminary mechanistic studies suggest their primary target is the mitochondrial respiratory chain. These findings support the potential of diiminoguanidines as affordable, mitochondria-targeting alternatives to existing pancreatic cancer therapies.