RSC medicinal chemistry最新文献

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.

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.

Several human cytochrome P450 enzymes (P450s) found in steroid/oxysterol biosynthesis are therapeutic targets to treat disease. This review article describes current research strategies to develop various inhibitors of three steroid P450s (P450s 17A1, 19A1, and 8B1) in order to benefit human health. (i) P450 17A1 (17α-hydroxylase/17,20-lyase) activity involves the hydroxylation at C17 and cleavage of the 17-20 bond to yield androgens. Abiraterone and galeterone are steroid inhibitors of P450 17A1, which both bear heterocycles (pyridine and benzimidazole) at C17 of the steroid moiety, the location of the enzymatic activity of P450 17A1. (ii) P450 19A1, the enzyme also known as aromatase, catalyzes the cleavage of the C10-C19 bond of androgens to give estrogens. Exemestane, which has the steroid structure of an androgen possessing an exocyclic methylene at C6, is a successful inhibitor of P450 19A1 used to treat breast cancer. (iii) P450 8B1 is the oxysterol-12α-hydroxylase enzyme that catalyzes the hydroxylation of the C12 position of its steroid based substrates. The hydroxylation of the C12 position ultimately forms the bile acid, cholic acid, which has implications in obesity. Mice lacking the gene for the expression of P450 8B1 resist weight gain and the inhibition of P450 8B1 activity has been suggested as a potential treatment of obesity. Studies towards a rationally designed inhibitor of P450 8B1 are described. This research in medicinal chemistry combines expertise in both organic synthesis and biochemistry, with the goal to improve human health.

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.

Interest in peptides and peptidomimetics continues to grow, particularly in the context of drug discovery and development. However, spontaneous chemical modifications such as deamidation and isoaspartate formation present significant challenges, as they are difficult to detect and can compromise peptide integrity and function. Conventional chromatographic methods and standard mass spectrometric analyses often fail to distinguish structurally similar peptides with nearly identical physicochemical properties and masses. In this study, tandem mass spectrometry (MS/MS) was employed to monitor deamidation events involving asparagine, glutamine and C-terminal amide functional groups. Both collision-induced dissociation (CID) and electron-transfer dissociation (ETD) were systematically evaluated and could differentiate the resulting species without relying on chromatographic separation, with ETD further enabling semi-quantitative detection of deamidation and isoaspartate formation. Using this approach, we confirmed isoaspartate formation under mildly basic conditions such as phosphate-buffered saline, whereas amidated peptides remained stable in neutral aqueous-organic mixtures or at lower temperatures. In contrast, exposure to acidic conditions, particularly in the presence of the additive trifluoroacetic acid, as commonly used during HPLC purification, resulted in substantial direct deamidation by hydrolysis without detectable isoaspartate formation. Notably, this degradation showed clear site dependence, with especially C-terminal amides, being markedly more susceptible in our study. These findings underscore how readily deamidation and isoaspartate formation can occur under routine laboratory conditions and highlight the utility of CID and ETD mass spectrometry for reliably detecting these modifications. The study emphasizes the need for careful analytical monitoring during peptide synthesis and purification to avoid misinterpretation of structural integrity.

Amino acid conjugates are progressively becoming popular as a potent tactic to enhance the pharmacological efficacy of drugs, especially in the areas of cancer and antimicrobial therapy. By taking advantage of the intrinsic biological attributes of amino acids, their conjugates facilitate drug stability, selective accumulation, and enhanced therapeutic efficacies. In particular, the structural analogy of amino acids to physiological substrates enables these conjugates to use solute carrier transporters, commonly overexpressed in tumour cells, which allow for targeted and effective drug delivery. This review considers how amino acid properties like chirality, hydrophobicity and steric bulk can be modulated to maximize drug conjugates. We emphasize important design aspects, such as selection of linkers and coupling reagents, and how these have an impact on drug release and biodistribution. Specific focus is given to D-amino acid, which increases proteolytic stability and bioactivity for both anticancer and antimicrobial uses, and to L-amino acid, which is responsible for receptor recognition, metabolic compatibility and amino acid decorated nanoparticle formulation. The existing drawbacks of antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) are immunogenicity, enzymatic degradation and poor tissue penetration. Amino acid conjugates provide a strong rationale with higher chemical versatility and potential for better pharmacokinetics and less toxicity. By harnessing the insights from chemistry, transporter biology and therapeutic design, this review presents a strategy for the creation of next-generation amino acid conjugates that bridge molecular accuracy to clinical utility.

Recent advances in medicine and drug development have significantly changed how cancer is treated. The success of inhibitors like sotorasib and adagrasib has expanded options for targeting once 'undruggable' oncogenic drivers such as KRAS. The emergence of RET and NTRK inhibitors shows the increasing importance of targeted therapies. Recent developments in immunotherapy include new immune checkpoint inhibitors (LAG-3, TIGIT, and TIM-3), which enhance the efforts to combat cancers that evade immune detection. ADCs such as EMRELIS™, Datroway, and ELAHERE™ offer precise targeting along with potent cytotoxic agents. Protein degradation strategies, using the ubiquitin-proteasome system, provide new ways to remove oncogenic proteins through PROTACs and molecular glues. Epigenetic drugs such as IDH and EZH2 inhibitors seek to correct transcriptional dysregulation in cancer. New tactics to overcome resistance, including EGFR C797S inhibitors and combination therapies, aim to improve treatment durability. Cancer vaccine research is progressing with licensed immunoprophylactic drugs, and AI tools like AlphaFold are speeding up drug discovery by enhancing structural biology predictions. This review covers recent cancer therapeutics advancements, including targeted inhibitors, immunotherapies, resistance strategies, epigenetic interventions, combination therapies, vaccines, and AI applications.

Background: this study investigates the metastasis-promoting effect of colorectal carcinoma cell-derived exosomes in liver metastasis, M2-like polarization of Kupffer cells, and the underlying mechanism. Methods: mouse liver metastasis models were established to determine the involvement of CRC-derived exosomes in liver metastasis. The DIR and PKH26 fluorescent labeling strategies were utilized to trace the distribution of CRC-derived exosomes in vivo. GO and KEGG analyses of differentially expressed genes revealed the key cellular regulator and KRAS-induced signaling in CRC liver metastasis. The phenotype of Kupffer cells was determined by IHC and IF. In vitro model HMDMs were used to explore polarization phenotype and therapeutic effects of GSK690693 (AKT inhibitor) inhibited AKT. Results: exosomal mutant KRAS induced AKT signaling in the process of Kupffer cell M2-like polarization, promoting CRC liver metastasis. AKT inhibitors might potentially be used as a therapeutic approach to prevent liver metastasis in CRC. Conclusion: our findings reveal that exosomal mutant KRAS drives Kupffer cell M2-like polarization via the hyperactivation of AKT signaling, establishing this axis as a key mediator of colorectal cancer liver metastasis. Pharmacological inhibition of AKT effectively disrupts this immunosuppressive reprogramming, proposing targeted AKT blockade as a promising strategy to intercept the metastatic niche in CRC patients.

CDK8 is overexpressed in many cancers and represents a potential target for developing new anticancer agents. To identify promising antineoplastic compounds as CDK8 inhibitors, progesterone-heterocyclic conjugates were synthesized through multicomponent reactions (MCRs), verified by spectroscopic and analytical data, and they were then encapsulated into CS-PEG nanoparticles to enhance their activity and efficacy. The in vitro anticancer activity of synthesized progesterone heterocyclic derivatives in free and CS-PEG nanoform was assessed on A549 cells using the neutral red uptake test. Compared to Doxorubicin values (IC₅₀ = 11.74 and 10.14 μM for free and CS-PEG nanoform, respectively), compounds 4e, 4b, 4f, 13, 15, 8b, 12, and 4d, in free form (IC₅₀ = 3.63, 4.46, 5.49, 5.62, 9.54, 9.77, 10.47, and 10.96 μM, respectively) and in CS-PEG nanoform (IC₅₀ = 3.20, 3.54, 3.83, 5.28, 7.09, 9.43, 9.65, and 9.88 μM, respectively), showed higher inhibitory activity on A549 growth. Notably, compounds 4e and 4f showed significant inhibition of CDK8 enzyme in vitro comparable to Cortistatin A (IV). Furthermore, compounds 4e and 4f CS-PEG nanoparticles significantly downregulated the CDK8, β-catenin, c-MYC, and HIF-1α genes as well as the protein expression levels of PI3K and AKT, and also upregulated the levels of P53 gene and MDA in A549 cells, thereby triggering ROS-mediated apoptosis and suppressing angiogenesis, invasion, and cell growth. Additionally, the molecular docking study confirmed that compounds 4e and 4f had a strong binding affinity to the active site of CDK8, consistent with their results and antiproliferative activity on A549 lung cancer cells.