Medicinal Chemistry Research最新文献

In this work, we designed and synthesized 12 triphenylphosphonium (TPP) conjugates of acetylenated nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) and evaluated their in vitro cytotoxicity against 9 human cancer cell lines M-HeLa, HuTu 80, MCF-7, T 98 G, A 549, DU-145, SK-OV-3, PC-3, A-375 and two lines of normal human cells RPMI 1788 and WI-38. All synthesized TPP-conjugates showed high cytotoxicity (IC₅₀ values in the range of 0.1–7.3 µM) against all used human cancer cell lines. The mechanisms of cytotoxic action were studied for the lead compounds 2c,d, 4c,d which exhibited very high cytotoxicity (IC₅₀ = 0.2–0.3 μM) against PC-3 cancer cells. The flow cytometry method using Annexin V and propidium iodide (PI) has shown that the lead compounds cause apoptosis of PC-3 cells. With the help of flow cytometry using cationic carbocyanine dye JC-1, it was found that the lead compounds cause a significant dose-dependent decrease in the mitochondrial membrane potential of PC-3 cancer cells, that induces apoptosis along the mitochondrial pathway. Significant ROS production in PC-3 cells after their treatment with the lead compounds 2c,d was detected by flow cytometry using CellROX® Deep Red fluorogenic probe. Enzyme-linked immunosorbent assay (ELISA) found that the lead compounds activated apoptosis-initiating caspase-9 and blocked anti-apoptotic Bcl-2 protein in PC-3 cancer cells. This experimental fact was explained by molecular docking.

Wedelia species (the Asteraceae family) are renowned for treating several inflammation-related diseases clinically, such as pertussis and pharyngitis. Plants of the genus contain diverse bioactive metabolites. The review comprehensively describes scientific investigations regarding Wedelia species, comprising phytochemical record, pharmacological value, toxicological evaluation, and nano- and semisynthetic preparations. Four online sources Web of Science, Scopus, Google Scholar, and PubMed have been extensively used in the search for English references. The phytochemical profile of Wedelia species consisted of 290 secondary metabolites, which can be classified as terpenoids, phytosterols, saponins, phenolics, and others. Sesquiterpenoids and ent-kaurane diterpenoids were the major compounds. Wedelia species are also rich in terpenic essential oils. Wedelia constituents have a broad panel of pharmacological activities, such as anticancer, anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antinociceptive, and antiviral activities. It is also useful in applications that protect the neurons, liver, and bones, and aid in wound healing. Bezofuran, wedelolactone, and two major diterpenoids, kaurenoic acid and grandiflorenic acid, are likely the bioactive molecules. Various molecular mechanisms of anti-inflammatory action have been proposed, including the nuclear factor kappa B/mitogen-activated protein kinase (NF-κB/MAPK) signaling pathway. Wedelia extracts were associated with an LD₅₀ value of more than 2000 mg/kg to rats. Nanoformulation and semisynthesis would enhance the pharmacological activities of Wedelia. In vitro and in vivo pharmacological studies for a vast number of Wedelia isolates are encouraged. Developing new formulations with more therapeutic value is expected.

The DPPH radical scavenging, α-glucosidase inhibitory, nitric oxide (NO) inhibitory, and cytotoxic activities of the extracts from fruiting bodies of wood-rot basidiomycete Fulvifomes fastuosus were evaluated in this study. While the CH₂Cl₂ extract was biologically inactive, chromatographic fractionation led to the isolation of two chlorinated hydroquinone derivatives, drosophilin A methyl ether (DAME; 1) and drosophilin A (DA; 2). The EtOAc-partitioned fraction, obtained from the partitioning of the MeOH extract, exhibited strong α-glucosidase and NO inhibitory activities. Further investigation led to the isolation of inoscavin A (3) as the major constituent, along with inoscavin E (4) and polyphenols (5–7). Inoscavin A demonstrated potent α-glucosidase inhibition (IC₅₀ = 3.22 µM), surpassing acarbose by 59-fold, and exhibited non-competitive inhibition kinetics (Kᵢ = 3.25 µM). Molecular docking studies supported an allosteric binding mode. It also displayed favorable drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, including good solubility, high intestinal absorption, low central nervous system (CNS) penetration, and absence of hepatotoxicity. These results suggest that F. fastuosus is a promising source of antidiabetic agents, with inoscavin A as a principle active compound.

Formononetin (FMN), a natural isoflavone with broad biological activity, has emerged as a potential lead molecule as an anticancer agent. In this work, different FMN ester derivatives were synthesized via an acylation reaction (3a-d). The structural characterization and purity of the compounds were confirmed through NMR, HRMS, and HPLC analysis. Among the synthesized derivatives, the 4-Morpholinecarbonyl chloride conjugated FMN (FMN-4Morpho; 3b) demonstrated significantly (p < 0.05) enhanced cytotoxicity against multiple cancer cell lines, including A549, B16F10, and 4T1, while showing no notable toxicity up to 200 μM in non-cancerous L929 fibroblasts and RAW 264.7 macrophages, indicating good biocompatibility. The mechanistic evaluations in A549 and 4T1 cells revealed elevated ROS production, disruption of mitochondrial membrane potential, and increased apoptosis, as revealed by JC-1 and Annexin V-FITC/PI staining. Additionally, FMN-4Morpho suppressed colony formation and cell migration, downregulated cyclin A, cyclin D1, MMP-2, and MMP-9, and upregulated p53 and Bax expression, thereby lowering the Bcl-2/Bax ratio. The findings highlight FMN-4Morpho as a promising therapeutic candidate with improved anticancer efficacy.

Inflammation plays a crucial role in the onset and progression of various diseases. However, current anti-inflammatory therapies often produce adverse effects that limit their clinical utility. This review focuses on the therapeutic potential of iridoid glycosides, a class of monoterpenoid compounds known for their anti-inflammatory properties. Drawing on literature from PubMed and Google Scholar, this study comprehensively examines eight well-studied iridoid glycosides in terms of their sources, administration methods, dosages, target inflammatory models, and mechanisms of action. The compounds were found to modulate critical signaling pathways, including NF-κB, NLRP3 inflammasome, MAPK, and JAK-STAT, thereby suppressing key inflammatory cytokines such as TNF-α, IL-1β, and IL-6, while also activating antioxidant defenses. Structure–activity relationship analysis suggests that glycosyl, ester, and epoxy groups are essential pharmacophores for their bioactivity. Collectively, these findings underscore the promise of iridoid glycosides as effective and safer alternatives for managing inflammatory diseases.

As a novel therapeutic strategy, targeted protein degradation (TPD) enables the selective elimination of disease-driving proteins through endogenous degradation pathways such as the ubiquitin-proteasome system and lysosomal trafficking. However, the therapeutic potential of TPD agents is often limited by poor solubility, low bioavailability, off-target toxicity, and inefficient intracellular delivery. Nanocarrier-based delivery systems offer a promising solution to these challenges by enabling controlled release, enhanced pharmacokinetics, and precise intracellular trafficking of TPD agents, including PROteolysis TArgeting Chimera (PROTACs), LYsosome-TArgeting Chimeras (LYTACs), or AUtophagy-TArgeting Chimeras (AUTACs). These systems can be engineered to respond to tumor-specific internal stimuli (e.g., pH, redox environment, enzymes) or external triggers (e.g., light, ultrasound, magnetic fields), enabling spatiotemporal control of drug release while minimizing systemic toxicity. Furthermore, modular nanocarrier designs allow for co-delivery with synergistic therapeutics, improved endosomal escape, and surface modification for cell-specific targeting. Recent innovations, including the development of exosome-based and carrier-free nanotechnology-enabled TPD platforms (Nano-TPDs), further expand the landscape of degradable targets and therapeutic indications. This review highlights the design principles, current advances, and future directions of nano-TPD systems, with an emphasis on their potential to overcome delivery barriers and redefine precision oncology.

Cytochrome P450s (CYP450s) are a diverse and functionally rich family of heme-containing enzymes that play vital roles in the metabolism of endogenous and xenobiotic compounds. In recent years, microbial CYP450s have gained attention for their potential in environmental bioremediation due to their ability to oxidize a wide range of chemically complex and recalcitrant pollutants. This mini-review provides an overview of CYP450s and highlights their emerging roles in the degradation of selected environmental pollutants, including pharmaceuticals, personal care products (PPCPs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs). We further discuss recent advances in CYP450 discovery enabled by metagenomic mining, sequence similarity networks, and machine learning/artificial intelligence (ML/AI), along with innovations in enzyme engineering through rational design, site-directed mutagenesis, and ML/AI-guided directed evolution. Collectively, these developments illustrate the growing potential of microbial CYP450s as sustainable biocatalysts for tackling complex environmental contaminants.

This study employed structure-based drug design to discover novel inhibitors of Adaptor Associated Kinase 1 (AAK1) as potential anticancer agents. A total of 300 pharmacophore models were generated from AAK1 co-crystallized protein structures, from which the optimal model (Hypo1) was selected based on receiver operating characteristic (ROC) analysis (AUC = 82.3%) and further refined using shape-based alignment. Virtual screening of the National Cancer Institute (NCI) database yielded 7399 initial hits, which were narrowed down to 3481 compounds through Lipinski’s rule of five and SMARTS pattern filtering. Subsequent molecular docking against the AAK1 active site identified 438 candidates, of which the top 40 were selected for biological evaluation. Among these, Hit 5 (NCI 157865) exhibited the most potent AAK1 inhibition (IC₅₀ = 1.03 µM), with other active hits showing IC₅₀ values ranging from 1.87 to 7.49 µM. MTT assays confirmed the anticancer activity of Compound 5, with IC₅₀ values of 11.46 µM against MCF7 and 69.37 µM against A549 cell lines. The compound’s potency is attributed to key hydrophobic interactions and hydrogen bond acceptor features. These results highlight Compound 5 as a promising lead candidate for further development as an anticancer agent.

Hypo1 fitted against hit 5 as compared to its 2D interactions within AAK1 binding site with IC₅₀ = 1.05 μM

Saponin-based adjuvants have emerged as promising candidates for enhancing vaccine efficacy by modulating immune responses. Derived primarily from plant and marine sources, saponins possess unique amphiphilic structures that contribute to their potent immunostimulatory properties. This review explores the advancements in saponin-based vaccine adjuvants, focusing on their immunomodulatory mechanisms, structural diversity, and applications. QS-21, a triterpenoid saponin from Quillaja saponaria, is the most extensively studied and has been incorporated into licensed vaccines such as Shingrix, Mosquirix, and Arexvy. However, the limitations of natural saponin-derived adjuvants, including hemolytic toxicity, hydrolytic instability, and low yield, have driven research toward semi-synthetic and synthetic analogs. Advances in synthetic biology and biosynthetic pathway elucidation have enabled the development of next-generation saponin-based adjuvants with enhanced potency and reduced toxicity. This review provides a comprehensive overview of the current state of saponin-based adjuvant research, highlighting their potential to revolutionize vaccine formulations and contribute to global public health initiatives.