Anti-Cancer Agents in Medicinal Chemistry - Online First

Ovarian cancer (OC) is a lethal gynecological malignancy, with current therapies constrained by drug resistance and side effects. Autophagy plays a dual role in OC, while Traditional Chinese Medicine (TCM) monomers, as natural bioactive compounds, demonstrate significant potential in regulating autophagy and combating tumors. This review aims to summarize the mechanisms by which TCM monomers regulate autophagy in OC, providing a theoretical basis for TCM-based drug development and clinical applications.

Relevant literature was retrieved from databases including PubMed, Web of Science, and CNKI. The action targets and signaling pathways of TCM monomers were summarized to elucidate their mechanisms in regulating OC autophagy.

TCM monomers (e.g., ginsenoside Rg3, curcumin) bidirectionally regulate OC autophagy through pathways such as PI3K/AKT/mTOR and MAPK; some enhance chemotherapy sensitivity by inducing excessive autophagy or inhibiting protective autophagy.

TCM monotherapy offers unique advantages in the treatment of OC through precise regulation of autophagy. However, most studies are limited to in vitro experiments, and there is insufficient in vivo efficacy and clinical translational evidence.

Validating the complex action network of TCM monomers through multi-omics and clinical studies, and exploring their synergistic effects with conventional chemotherapy, is crucial for advancing the development of natural anti-ovarian cancer drugs.

Mentha spicata L. (Lamiaceae) has been used in traditional medicine to cure indigestion, stomach aches, and diarrhea. This research aims to synthesize silver nanoparticles from aqueous extract of M. spicata and to investigate its antioxidant, antibacterial, and anticancer activities.

The plant was extracted using maceration with water, and Mentha spicata-silver nanoparticles (MAgNPs) were prepared using a 5 mM silver nitrate solution. The antioxidant activity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide scavenging assays. Antibacterial analysis was done through the agar disk diffusion method. The anticancer potential was evaluated using the cytotoxicity and MTT assays.

The phytochemical screening revealed the presence of flavonoids and other phenolic compounds. The aqueous extract and silver nanoparticles scavenged the DPPH and hydrogen peroxide free radicals, with IC50 values of 1.556 mg/mL and 1.695 mg/mL, respectively. The bacterial strains were susceptible to the extract and silver nanoparticles, with inhibitory zones ranging from 4 to 11 mm. The zeta analysis revealed a size of 70.08 nm and a potential of -13.17 mV. The XRD showed a crystalline structure of silver nanoparticles. The FTIR revealed a characteristic N-H stretching frequency. The extract and nanoparticles exhibited cytotoxic and anti-proliferative effects in vitro against MDA-MB-231 cancer cells, with a significant difference among means (p < 0.05).

There is an urgent need to screen and standardize medicinal plants with medicinal benefits and less toxicity, which also serve as chelating agents in drug delivery.

The ability of the extract to scavenge free radicals and inhibit bacterial growth may be due to its chemical constituents. MAgNPs may be a viable option for potential application and development in cancer therapy.

During the last 20 years, the prevalence of colon cancer, among the most prevalent gastrointestinal cancers globally, has increased in the majority of nations. The current review compiled phytochemicals reported to manage colon cancer from 2015 to 2020.

The article is taken from various sources of Web of Science, PubMed, Google Scholar, Scopus, Elsevier, Research Gate, and PubChem.

Colon cancer is the leading cause of cancer-related death worldwide and impacts both men and women. Because of the present dietary habits and lifestyle, which include eating a lot of meat, drinking alcohol, and not exercising enough, the death rate from colon cancer has increased globally. A robust gastrointestinal tract and the control of regular intestinal activity seem to be significantly influenced by dietary fiber.

The prognosis for colon cancer is dismal, as it is frequently discovered at an advanced stage. Despite some evidence suggesting a diet low in fibre predisposes to colon carcinogenesis. The use of phytochemicals may help in the management of colon cancer.

By altering many signalling pathways involved in the control of chronic inflammation, the cell cycle, autophagy, apoptotic metastasis, and angiogenesis, these natural compounds have been shown to have anti-colon cancer properties. Compounds such as Ellagitannin, Ursolic acid, Garcinol, Oxymatrine, Emodin, Catalpol, Resveratrol, Zerumbone, Curcumin, Pyrogallol, α-Hederin, Juglone, Zingerone, Brosimone I, Organosilicon, Myricetin, Tenacissoside H, 6,8-Diprenylorobol, Plumbagin, Dioscin, and many more are listed with their mechanisms of action.

Heterocyclic compounds are widely utilized in the development of anticancer medications due to their diverse structures and ability to interact with multiple biological targets within cancer cells. Quinoline is a heterocyclic compound and an essential compound in the domains of industrial and pharmaceutical chemistry because of its various pharmacological effects. Researchers are developing new traditional, synthetic, and innovative green approaches to synthesize mono- or poly-substituted quinoline derivatives for anticancer activity.

A comprehensive literature survey was conducted using multiple databases, including Google Scholar, PubMed, SpringerLink, ScienceDirect, and others, to investigate the existing literature on synthetic strategies for various quinoline derivatives. This review article intends to present a summary of various traditional synthetic methods alongside innovative green approaches.

Many researchers have demonstrated that quinoline derivatives can be synthesized using various methods, including traditional techniques, hybrid approaches with heterocyclic structures, and innovative green synthetic methods, as well as elucidating their structure-activity relationships for potential use as anticancer agents. The majority of traditional synthetic methods rely on hazardous chemicals, low reaction rates, high temperatures, and high pressures. Currently, the green chemistry approach produces eco-friendly, economical, high-yield, pure, and outstanding products in the fields of industry and pharmaceuticals.

This section explores various affordable and eco-friendly synthetic techniques that produce potent and specific quinoline compounds, intended for use as anticancer agents.

The progress demonstrated in the green synthetic methods and the development of quinoline-based compounds as new treatment options could aid in identifying new and effective quinoline derivatives for cancer treatment in the future.

Estrogen receptor (ERa) is known to be a legitimate therapeutic target for the treatment of ER-positive breast cancer. Although selective estrogen receptor degraders (SERDs) like fulvestrant suppress ER signaling, their limited bioavailability challenges efficacy. Additionally, activating mutations in the ERa mediate resistance to endocrine therapy.

To elucidate the structural activity relationship within a chromene-based scaffold, we conducted pharmacophore mapping and Gaussian field-based 3D QSAR modelling. The most active analogue was docked into the ERa ligand binding domain (PDB ID: 6V8T) and then subjected to molecular dynamics simulations and molecular mechanics generalized born surface area (MM/ GBSA) binding-free energy calculations.

The pharmacophore mapping produces a five-point hypothesis, of which HHHRR_1 achieved the highest survival score (6.423) with a fitness score close to 3. Using HHHRR_1, a Gaussian Field-based 3D QSAR model with strong internal predictivity (cross-validated q² is 0.8) and an excellent external validation was developed (r² is 0.94). Compound 18 demonstrated stable binding in the ERa pocket with a ΔGbind MM/GBSA value of -67.03 kcal/mol, outperforming fulvestrant with a ΔGbind MM/GBSA of -64.76 kcal/mol. These findings suggest compound 18 engages critical ERa interactions more effectively with the target.

The integrated modelling approach, like pharmacophore mapping, 3D QSAR, docking, and molecular dynamics, elucidated molecular characteristics essential for potent ERa degradation. Compound 18, having superior binding affinities, implies that optimizing these features on a chromene scaffold can yield new oral SERDs with enhanced therapeutic potential.

Based on the results of pharmacophore mapping, docking, molecular simulation, and 3D QSAR studies, we have designed a new set of chromene scaffold-based derivatives as potent SERDs along with their predicted activity.

Prostate cancer is a leading cause of cancer-related mortality in men worldwide, and the treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. CD24, a glycosylated cell surface protein, plays a critical role in tumor progression and immune evasion. This review focuses on the role of CD24 in prostate cancer pathogenesis, particularly its interaction with mutant p53, and explores potential therapeutic implications.

Through a systematic search of the PubMed, Web of Science, and Embase databases (2015–2025), using the following structured search terms: (CD24 OR “CD24 antigen”) AND (“prostate cancer” OR “prostatic neoplasms”) AND (“mutant p53” OR “TP53 mutation”) AND (“targeted therapy” OR immunotherapy), relevant studies were identified and screened according to PRISMA guidelines.

CD24 overexpression was significantly associated with high Gleason scores, metastasis, and poor prognosis. Mechanistically, CD24 promotes tumor progression by destabilizing p53 through the disruption of ARF-NPM interactions and by synergizing with mutant p53. Preclinical studies indicate that therapies targeting CD24, such as CAR-T cells and nanoparticle-based drug delivery systems, demonstrate potent anti-tumor effects.

The CD24–p53 axis is amplified in mCRPC and interacts with androgen receptor signaling, while tumor microenvironment factors further enhance treatment resistance.

CD24 and mutant p53 represent promising therapeutic targets in metastatic castration-resistant prostate cancer (mCRPC). Translating these targeting strategies into clinical practice may help overcome current therapeutic challenges and improve patient outcomes.

The emergence of acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) presents a significant barrier to effective treatment in lung adenocarcinoma. This study investigates the antitumor efficacy of FN-1501 and its potential synergistic interaction with Almonertinib (Alm) to combat this resistance.

The impact of FN-1501 on lung adenocarcinoma and its synergistic effects with Almonertinib (Alm) were assessed through flow cytometry, Western blot analysis, CCK-8 assays, and clonogenic formation assays. Additionally, transcriptome analysis and network pharmacology were employed to elucidate the functional mechanisms by which FN-1501 may reverse EGFR-TKI acquired resistance.

FN-1501 demonstrated the ability to inhibit cell proliferation, induce apoptosis, and arrest the cell cycle. The combination of Alm and FN-1501 restored sensitivity in resistant cell lines. Mechanistic investigations indicated that this combination triggered ferroptosis via the FOXO1-mediated upregulation of NCOA4. In vivo experiments showed that the Alm+FN-1501 combination significantly inhibited tumor growth compared to either treatment alone.

These results provide compelling evidence that targeting ferroptosis pathways could be a viable approach to overcoming resistance to EGFR-TKIs. The FOXO1/NCOA4 axis emerges as a critical component in this process, enhancing our understanding of the mechanisms underlying resistance. While these findings are promising, further research is needed to evaluate toxicity, pharmacokinetics, and the applicability of this strategy in a broader context of resistance. Identifying predictive biomarkers could help refine patient selection for this treatment approach.

FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.

Hypopharyngeal Squamous Cell Carcinoma (HSCC) is associated with a poor prognosis due to challenges in early detection, early metastasis, and limited treatment options.

This study aims to investigate the effect of metformin on HSCC and identify potential prognostic factors associated with this carcinoma.

The effects of metformin in HSCC cells were tested by functional assays in vitro. A xenograft tumor model was established, which was further examined by H&E staining, immunohistochemistry, and transmission electron microscopy (TEM). RNA sequencing analysis was employed to investigate the effects of metformin on gene expression and associated pathways. Bioinformatic analysis was further conducted to elucidate potential mechanisms and their correlation with gene expression, the tumor immune microenvironment, and survival prognosis. Finally, we further assessed the effect on FaDu cells by knocking down lncAROD using siRNAs.

The results demonstrated that metformin significantly reduced cell viability and migration, while promoting apoptosis and inducing cell cycle arrest in FaDu cells. WB analysis revealed that metformin inhibits the development of FaDu cells, possibly through the EMT pathway. In vivo studies indicate that metformin effectively inhibits tumor growth, promotes apoptosis, and autophagy. RNA-seq analysis revealed that metformin led to the upregulation of 1,697 genes and the downregulation of 858 genes, particularly highlighting a significant reduction in lncAROD, which were subsequently verified by qRT-PCR. Bioinformatic analysis demonstrated that lncAROD is highly expressed, with patients exhibiting higher levels of lncAROD showing poorer prognoses. Knockdown of lncAROD can reduce the proliferation, migration, and invasion of FaDu cells.

This finding presents a novel approach to the clinical management of HSCC, indicating that metformin influences various processes related to the growth and progression of HSCC. Specifically, it reduces lncAROD expression and inhibits tumor progression, suggesting that lncAROD may serve as a valuable biomarker for evaluating the prognosis of HSCC.

Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) develop primary resistance or relapse, owing to the high heterogeneity and aggressive nature of the disease. Consequently, novel drugs are urgently needed to improve outcomes in patients who are resistant.

This study quantified the anti-proliferative effects of CCS1477 in vitro using the Cell Counting Kit-8 assay, 5‐ethynyl‐2′‐deoxyuridine staining, and lactate dehydrogenase measurement. Flow cytometry and Western blot analyses were performed concurrently to investigate the induction of apoptosis and the activation of mitophagy. The efficacy and safety of CCS1477 were evaluated in in vivo models. To elucidate the mechanism, cell lines with EP300 knockdown and overexpression were established. Functional assays and Western blot analyses revealed that EP300 regulates apoptosis, mitophagy, and c-MYC-mediated drug-resistant phenotypes.

This study demonstrated that CCS1477, a highly selective EP300/CBP bromodomain inhibitor, significantly suppressed the progression of diffuse large B-cell lymphoma. The study revealed that CCS1477 dose-dependently inhibited the proliferation of diffuse large B-cell lymphoma cells and induced apoptosis and mitophagy. Mechanistically, EP300 downregulation promoted apoptosis and activated the PINK1-dependent mitophagy pathway while suppressing c-MYC-mediated drug resistance genes, ultimately inhibiting DLBCL cell proliferation. In animal models, CCS1477 significantly reduced tumor volume and extended doubling time, providing the first evidence of its in vivo antitumor activity against DLBCL.

Through systematic in vitro and in vivo investigations, this study validated the significant therapeutic promise of EP300/CBP inhibitor CCS1477 for diffuse large B-cell lymphoma. However, the mechanistic basis for differential sensitivity across DLBCL subtypes, along with long-term efficacy and potential adverse effects, requires comprehensive investigation. Notably, EP300 has been verified as a novel prognostic biomarker and therapeutic target; this work establishes an innovative epigenetic-targeted strategy for relapsed/refractory diffuse large B-cell lymphoma.

By selectively targeting EP300, CCS1477 orchestrates a dual pro-death mechanism involving both intrinsic apoptosis execution and PINK1-driven mitochondrial clearance, resulting in significant inhibition of diffuse large B-cell lymphoma pathogenesis.

The emergence of immune checkpoint inhibitors has revolutionized the treatment of cancer. Among these, the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis remains a critical target. However, resistance to current biologics necessitates the development of novel Small-Molecule Inhibitors (SMIs) with distinct mechanisms and improved pharmacological profiles. This review provides a comprehensive analysis of recent progress in PD-L1-targeting SMIs, including original compounds from our laboratory.

We conducted a structured literature review using electronic databases such as PubMed, Scopus, and Web of Science. Articles published between 2015 and 2025 were included based on relevance to small-molecule PD-L1 inhibitors in cancer immunotherapy. Key data were extracted and synthesized regarding molecular design strategies, mechanisms of action, pharmacokinetics, and therapeutic efficacy. Compounds synthesized in our laboratory (Compounds 5–10 [A56]) were evaluated using in vitro assays, including PD-L1/PD-1 binding inhibition, cancer cell viability assays, and gene expression profiling.

Recent SMIs exhibit diverse functional profiles: direct blockade of PD-1/PD-L1 interaction, intracellular PD-L1 modulation, and transcriptional downregulation. Notably, Compound 7 demonstrated significant suppression of PD-L1 mRNA expression, while Compounds 9 and 10 (A56) achieved nanomolar-level binding affinity. These findings reflect innovative approaches to overcoming immune resistance and enhancing antitumor responses.

Our findings underscore a trend toward multifunctional PD-L1-targeting SMIs that operate through both extracellular and intracellular mechanisms. Compounds from our laboratory represent potential leads for further optimization and clinical translation. However, challenges remain regarding oral bioavailability, metabolic stability, and immune-related adverse events.

Small-molecule PD-L1 inhibitors offer a promising avenue for expanding cancer immunotherapy. Our review highlights key advances and introduces novel small-molecule PD-L1 inhibitors with strong potential for future development, particularly in combination regimens.