Anti-Cancer Agents in Medicinal Chemistry - Online First

Heterocyclic compounds serve as the structural framework for many commercially available drugs and are well known for their antitumor properties.

This study aimed to evaluate the cytotoxic effects, apoptosis induction, changes in cell cycle progression, and gene expression alterations of new heterocyclic compounds and their precursors against the acute monocytic leukemia cell line THP-1 through in vitro experimentation and computational approaches.

The study employed cytotoxicity assays, flow cytometry analyses, gene expression evaluations, oral bioavailability studies, and molecular modeling. Among the compounds tested, 6, 25, and 26 demonstrated the greatest potency and selectivity, exhibiting substantially increased cytotoxicity (1.18 μM < IC50 < 7.66 μM) against the THP-1 cell line. Investigations into apoptosis induction and cell cycle changes revealed that these compounds primarily caused an increase in the number of THP-1 cells undergoing apoptosis after 48 hours of treatment. Additionally, compounds 6 and 25 induced an accumulation of cells in the G0/G1 phase in the same cell line.

Regarding gene expression, a shift in the expression profile of genes associated with apoptotic mechanisms was observed. Furthermore, in silico analysis revealed that these three active compounds potentially interact with histone deacetylase 8 (HDAC8), a protein known to be associated with cancer.

These findings underscore the potential of these compounds as candidates for the development of novel therapeutic approaches in oncology.

Cancer is a complex disease marked by changes in the levels and functions of key cellular proteins, including oncogenes and tumor suppressors. Proteomics technology enables the identification of crucial protein targets and signaling pathways involved in cancer cell proliferation and metastasis. Various proteomics techniques have been employed to investigate the molecular mechanisms of cancer, aiding in the confirmation and characterization of heritable disorders.

A comprehensive literature search was conducted using PubMed, ScienceDirect, and Google Scholar with search terms like “Cancer and proteomics” and “Mass spectrometry in oncology,” utilizing Boolean operators for refinement. Selection criteria included peer-reviewed articles in English on MS-based biomarker detection, tumor-specific proteins, and drug resistance markers, excluding non-peer-reviewed works and pre-2000 publications unless foundational. Extracted data focused on MS methodologies, biomarker sensitivity, and clinical applications, particularly advances in detecting low-abundance biomarkers and monitoring treatment response. Methodological quality was assessed using PRISMA, evaluating study design, sample size, reproducibility, and statistical analysis. Ethical approval was not required, but adherence to systematic review guidelines and proper citation were ensured.

In this review, we highlighted the advanced analytical technique for cancer diagnosis and management of cancer, and described the objective of novel cancer biomarkers. Mass spectrometry (MS) is transforming cancer diagnostics and personalized medicine by enabling precise biomarker detection and monitoring. Unlike traditional antibody-based methods, MS provides high-throughput, quantitative analysis of tumor-specific proteins in clinical samples like blood and tissue. Advanced MS techniques improve sensitivity, allowing for the identification of low-abundance biomarkers and tumor-associated proteoforms, including post-translational modifications and drug resistance markers. In research, MS-based proteomics supports multi-center biomarker validation studies with standardized protocols, enhancing reproducibility. The integration of proteomic data with genomic and transcriptomic datasets through proteogenomics is refining precision oncology strategies. These advancements are bridging the gap between research and clinical application, making MS a critical tool for early cancer detection, prognosis, and therapy selection.

Advancements in technology and analytical techniques have helped to produce more accurate and sensitive cancer-specific biomarkers. These methods are advancing rapidly, and developing high-throughput platforms has yielded great results. However, the substantial variation in protein concentrations makes cancer protein profiling extremely complicated. This shows that more technical developments are required in the future to improve proteome broad screening of cancer cells.

Lung cancer is one of the most widespread malignancies among all types of cancers. There is uncertainty in its treatment because of the selectivity. The investigation is aimed to enhance therapeutic efficacy through targeted improvements in drug selectivity and reduced toxicity by analyzing well-accepted cyclooxygenase (COX)-2, which is an enzyme target and a known therapeutic target for anti-inflammatory and antitumor agents.

The objective of the present research was to identify the most suitable counterpart for celecoxib, which would produce synergistic effects and improve the selectivity index, safety, and efficacy of targeting cancer cells.

The HOPE-62 cancer cell line and noncancerous LLC-MK2 cell line were used to analyze the activity of the prepared formulations. The effectiveness was compared by calculating the half-maximal inhibitory concentration (IC50) values of carrageenan, celecoxib, and celecoxib embedded with carrageenan. The release pattern of celecoxib from the carrageenan matrix was also determined by using a trans-diffusion cell; moreover, the binding sites of carrageenan and celecoxib were also evaluated through in silico molecular docking studies.

Carrageenan showed promising anticancer activity, with an IC50 value of 17.3±2 µM against the HOPE-62 cell line. When blended with celecoxib (15.6±2 µM), the combination achieved enhanced efficacy and improved selectivity over celecoxib alone (IC50 of 10.3±1.5 µM). In noncancerous LLC-MK2 cells, the IC50 values were observed to be significantly higher: 1484 ±6 µM in the combined formulation and with IC50 values of 559±3 µM and 878±4 µM, respectively, in celecoxib and carrageenan alone.

The carrageenan-embedded celecoxib exhibited a significant increase in the selectivity index from 32 to 144, which suggests enhanced anticancer activity with a favorable safety profile. Initially, sustained release of celecoxib from the blend was at a higher rate, but steadily maintained rates were. The In-silico docking studies also supported the synergistic activity of the combined form through separate interaction patterns without interfering with others. These findings underscore the therapeutic potential of excipient–drug blending strategies to achieve synergistic effects, excellent selectivity, and reduced toxicity in cancer treatments.

Aurone based compounds exhibited antioxidant and anti-inflammatory potential and documented for their anticancer potential. The anticancer potential of aurone derivatives AU3, AU4, AU5, AU7, and AU10 is yet to be studied against breast cancer.

The present work was undertaken to evaluate the anticancer potential of aurone based test compounds AU3, AU4, AU5, AU7, and AU10 in breast cancer cell lines MCF-7.

The azaindole based aurones were synthesized by the condensing 4,6-dimethoxybenzofuran-3(2H)-one derivative with various indole aldehydes in the presence of sodium hydroxide. The MCF-7 breast cancer cell line was used to assess the cytotoxic effects of these compounds. Molecular docking studies of the synthesized compounds against the Cyclin-dependent kinase 2 (CDK2)/Cyclin A complex were conducted.

Our experimental findings demonstrated that AU3, AU4, AU5, AU7, and AU10 elicited significant effects on MCF-7 by virtue of its minimum cell viability, with IC50 values of 70.14 µM, 87.85 µM, 133.21 µM, 52.79 µM, and 99.55 µM, respectively, thus, exhibits potential anticancer action. Further, to corroborate the anticancer potential, we investigated mechanisms of action through molecular docking studies with the CDK2/Cyclin A complex (PDB: 6GUC) and their findings demonstrated that test compounds showed robust binding through various interactions, including hydrogen bonds, Pi-interactions, and Alkyl bonds with key residues such as Lys129, Asp127, Gln131, and Asp145. Test compounds AU3 and AU7, exhibited better binding affinities and diverse interaction profiles, suggesting a potent disruption of CDK2/Cyclin A activity.

Thus, in conclusion, our findings revealed that AU3, AU4, AU5, AU7, and AU10 elicited anticancer action and their effects through CDK2/Cyclin A disruption.

Although the development of SHP2 inhibitors has made striking progress, there is no inhibitor in clinical evaluation because of the potential side effects induced by poor drug distribution. Fluorescence imaging technology is widely used in the process of diagnosis and treatment of diseases because of the advantages of rapid imaging and non-destructive detection and might provide a new way to explore the mechanism of drug-target interactions in intact tissue.

A series of 2-quinolone derivatives as fluorescent inhibitors against SHP2 were designed and synthesized, and their spectral properties and biological activities were evaluated in this report. The representative compound 8A had excellent fluorescence properties (: 562 nm, Stokes shift: 170 nm, fluorescence quantum yield: 0.072) and optical stability.

Moreover, compound 8A emitted a blue signal in SHP2^WT U2OS cells and inhibited the SHP2 enzyme abilities (IC50: 20.16 ± 0.95 μM) without the extra combination of suitable fluorophores, linker, or selective-activated molecules.

Therefore, we hope that compound 8A could act as a lead to develop novel, convenient, and bifunctional chemical tools to explore the mechanism of drug-target interactions in intact tissue and promote the integrated research progress of diagnosis and treatment of SHP2 related diseases.