Medicinal Chemistry Research最新文献

Hydroxypyranone ligands, in particular maltol and kojic acid, have proven to be promising building blocks in the development of transition metal-based anticancer agents. Their ability to chelate biologically relevant metal ions such as vanadium, copper, zinc and ruthenium enables the formation of stable coordination complexes with significant cytotoxic and pro-apoptotic activity. This review highlights the structural characteristics of hydroxypyranone ligands and their influence on the pharmacological properties of metal complexes. Notable systems, including bis(maltolato)oxovanadium(IV) (BMOV), VO–phen complex(Metvan) and Ru(II)–maltol complexes, have shown higher selectivity and lower systemic toxicity compared to classical chemotherapeutic agents such as cisplatin. The most important mechanisms of action include interaction with DNA, the formation of reactive oxygen species (ROS), mitochondrial dysfunction and the inhibition of enzymes. This review highlights the antitumor activity of copper(II), vanadium(IV/V), and ruthenium(II) complexes against hepatocellular and colorectal cancer cell lines. The review highlights the importance of rational ligand design, redox activity and metal ion selection for optimizing the therapeutic index of metallopharmaceuticals. Future perspectives point to the integration of these compounds into advanced drug delivery platforms and their evaluation in preclinical and clinical settings. This review emphasises the therapeutic importance of hydroxypyranone–metal complexes as selective and less toxic alternatives to platinum drugs. It provides new insights into their structure–activity relationships and supports their development as promising candidates for targeted cancer therapy.

Ivermectin is the most extensively researched macrocyclic lactone due to its potential anticancer and antiparasitic use. Nonetheless, there are more compounds within this family, including doramectin and abamectin. In the current era of medicinal repurposing, ivermectin has received renewed focus following its initial development for the treatment of parasitic conditions such as scabies, elephantiasis, and river blindness. Recent studies indicate that ivermectin may inhibit the proliferation of specific tumor cells by regulating many signaling pathways implicated in cancer progression. Despite the growing body of research on the topic, critical issues about its anticancer processes remain unresolved. Our study focused on ivermectin, its mechanisms of action, and its potential uses against glioblastoma multiforme (GBM).

The epidermal growth factor receptor (EGFR) is overexpressed in various cancers and contributes to tumor progression and therapeutic resistance. Although EGFR-targeting small-molecule inhibitors are clinically available, their limited efficacy and acquired resistance pose major challenges. In this study, we designed and synthesized a novel class of dual proteolysis-targeting chimeras (PROTACs) incorporating the natural product derivative Potassium Dehydroandrographolide Succinate (PDS) as the protein of interest (POI) ligand. PDS was selected as the POI ligand due to its structural similarity to andrographolide, a natural compound known to inhibit EGFR signaling, suggesting that PDS may retain EGFR-binding potential despite lacking direct anti-tumor reports. Unlike conventional PROTACs, these molecules feature two CRBN E3 ligase ligands symmetrically attached via distinct linkers, thereby enhancing the likelihood of ternary complex formation and promoting more efficient EGFR degradation. Among the synthesized compounds, DP6 exhibited the most potent anti-proliferative activity in MCF-7 cells, with a 3.8-fold improvement over the parent PDS molecule. Western blotting confirmed that DP6 induced concentration-dependent EGFR degradation via the ubiquitin–proteasome system, suppressed downstream JAK2-STAT3 signaling, and promoted apoptosis. This study not only demonstrates the feasibility of utilizing structurally modified natural products as POI ligands, but also introduces a unique dual-ligand PROTAC architecture that may provide enhanced degradation potency for traditionally “undruggable” targets.

We report the design and synthesis of PROTACs based on (3 R,4 R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)piperidin-3-ol, using diverse linkers and pomalidomide as a CRBN ligand. Molecular modeling experiments were conducted to arrive at the optimal exit vectors on both the warhead and pomalidomide to enable efficient linker attachment. Most of the PROTACs exhibited good binding affinity (IC₅₀ between 0.04 µM to 1.50 µM) with CDK4/6 and the binary complex formation data correlated with the ternary complex formation. Selected PROTACs (compounds 4, 7, and 13) were tested in Jurkat cells at varying concentrations to assess CDK4/6 protein degradation. Compound 7 showed a DC₅₀ of 2.0 and 4.0 nM against CDK4 and CDK6 respectively, whereas compound 13 showed a DC₅₀ of 6.0 nM against both CDK4 and CDK6. These results highlight PROTACs 7 and 13 as promising leads for further therapeutic development.

Photodynamic therapy (PDT) is a promising treatment for diseases like cancer and microbial infections, relying on light-activated photosensitizers to generate cytotoxic reactive oxygen species. While PDT has shown clinical success, developing novel photosensitizers with improved properties remains challenging. Ferrocene, with its unique stability, redox activity, and tunability, offers an attractive scaffold for this purpose. This review delves into the recent advancements in ferrocene-based photosensitizers, exploring their design strategies, mechanisms of action, and diverse applications in medicinal chemistry. We critically discuss their potential, comparing structure-activity relationships across various ferrocene derivatives and evaluating their performance in in vitro cell line assays. Additionally, we address current challenges and future directions, highlighting their potential to significantly advance PDT and offer new therapeutic avenues.

Neuroinflammation is increasingly recognized as an important pathological feature in numerous disorders of the CNS, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Many of the drugs used to treat CNS diseases display immunomodulatory properties. In this study, we demonstrate N-(alkyl)-4-arylpiperidine, a derivative of which is commonly found in CNS drugs, is an anti-neuroinflammatory pharmacophore. A series of N-(alkyl)-4-phenylpiperidines were evaluated for ability to suppress LPS-induced IL-6 levels in BV2 microglial cells. Several of these molecules showed activity and the results generated allowed for the delineation of a structure-activity trend and identified lead compound 4b. Further studies showed 4b suppressed various inflammatory mediators in BV2 cells, primary microglia, and T cells, including IL-6, TNF, IL-1β, and NO. Mechanistic studies demonstrated modulation of the NF-κB pathway as a potential mechanism of action. Taken together, our work shows N-(alkyl)-4-phenylpiperidines possess broad anti-neuroinflammatory activity and have potential in treating CNS disorders.

Formononetin, derived from Orostachys japonica (a traditional Chinese medicine), has been reported to have anti-cancer activity. In continuation of work on the exploration of formononetin derivative development, we designed and synthesized a novel series of formononetin-piperazine hybrids as anticancer agents, followed by evaluation of their antiproliferative activities against three cancer cell lines. Among these derivatives, compounds 6g (IC₅₀ = 5.87 ± 0.96 μM) and 6h (IC₅₀ = 3.50 ± 0.65 μM) emerged as the most potent analogues, demonstrating the best inhibitory activities against MGC-803 human gastric cancer cells. The structure-activity relationships (SARs) indicated that the introduction of substituents at meta-position of piperazine-linked phenyl moiety was helpful to enhance the anticancer potency. Further mechanistic investigations revealed that 6g and 6h exerted multimodal antitumor effects through G2/M phase arrest induction, apoptosis promotion, and migration suppression in MGC-803 cells. Thus, 6g and 6h could be deeply developed for the development of formononetin-based anti-cancer candidates.

Twenty-seven asiatic acid derivatives were designed and synthesized in this paper, including twenty-two new compounds. The synthesized compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The antitumor activities of all compounds against A549, Hela and HepG2 cancer cells in vitro were evaluated. Notably, AA-6a (IC₅₀ = 1.10 ± 0.25 μM) has better antitumor activity than gefitinib (IC₅₀ = 83.75 ± 1.72 μM) against A549 cells. AA-6b (IC₅₀ = 2.38 ± 0.36 μM) has better antitumor activity than gefitinib (IC₅₀ = 33.88 ± 1.51 μM) on Hela cells. AA-2b (IC₅₀ = 1.55 ± 0.21 μM) has the better antitumor activity than gefitinib (IC₅₀ = 48.37 ± 1.07 μM) against HepG2 cells.

Paeoniflorin is one of the active components of the root of peony, which has powerful and diverse pharmacological activities. However, low membrane permeability and gastrointestinal effects severely limit its absorption and bioavailability. In this paper, 190 paeoniflorin derivatives, including natural derivatives and synthetic derivatives, were collected. The pharmacological effects of the more active derivatives were summarized. In addition, the structure-activity relationship of paeoniflorin was appropriately summarized. This review aims to provide valuable assistance for further research and clinical application of paeoniflorin.

Plants have played a vital role in medicine from ancient times to the present. Many plant species have been used as medicinal remedies and as sources of bioactive compounds for modern pharmaceutical synthesis. The Tinospora genus, belonging to the Menispermaceae family, includes species such as T. cordifolia, T. sinensis, and T. crispa, which have long been utilized in traditional medicine, contributing significantly to human healthcare. Clinical evidence has further reinforced their potential as valuable sources of bioactive compounds for pharmaceutical development. A comprehensive review has been conducted based on publications over the past nine years to provide the latest insights into the phytochemistry and pharmacological properties of Tinospora species. Relevant literature was retrieved from databases such as PubMed, Google Scholar, and Web of Science (WOS) using keywords including “Tinospora”, “phytochemistry of Tinospora”, and “pharmacological activity of Tinospora”. From an initial pool of 150 related articles published between 2016 and 2025, 103 of the most relevant studies were selected. A total of nine Tinospora species have been analyzed in recent and ongoing research, revealing a diverse range of bioactive compounds, including terpenoids, steroids, lignans, alkaloids, phenylpropanoids, and benzenoids. Additionally, ten species have been investigated for their pharmacological activities, demonstrating notable effects such as neuroprotective and anti-neuroinflammatory activities, anti-inflammatory effects, anti-diabetic and anti-obesity properties, immunomodulatory functions, anticancer potential, larvicidal and antimalarial properties, and hepatoprotective effects. Toxicity and safety assessments have also been explored in several studies, further advancing our understanding of the medicinal applications of Tinospora species.