Anti-Cancer Agents in Medicinal Chemistry - Online First

Limited treatment options and poor prognosis create a need for new therapies for triple-negative breast cancer. Modulating lysine acetylation of histone and non-histone proteins via histone deacetylase inhibitors is a promising strategy in cancer therapy. This study aimed to design, synthesize, and test novel panHDAC inhibitors in vitro, building on our previous research.

Compound design was based on a previously validated diphenylmethyl piperazine scaffold, used as a template for further modifications. In silico studies included molecular docking and pharmacokinetic profiling for absorption, distribution, metabolism, excretion, and toxicity. Compounds identified from these analyses were synthesized, tested for in vitro enzymatic inhibition, and evaluated for cytotoxicity on cancer cell lines using the MTT assay.

Compound 8o had the strongest HDAC inhibitory profile. It was highly potent against HDAC6 (IC50 = 18.5 nM) and active against HDAC1 and HDAC8 (IC50 = 430 nM and 1620 nM, respectively). Compound 8p also inhibited HDAC6 (IC50 = 54 nM) but was less potent against the nuclear isoforms. Both compounds were less active than trichostatin A. In the cytotoxicity assay, 8o and 8p reduced the viability of triple-negative breast cancer cells in a dose-dependent manner. Compound 8o was the most active (IC50 = 6.74 μM on MDA-MB-231), exceeding the effect of tubastatin A. Moderate activity was seen on MDA-MB-468 cells.

In vitro enzymatic assays showed that compound 8o strongly inhibited HDAC6, similar to the reference compound 8b. However, its cellular activity did not exceed 8b, suggesting that factors other than target engagement may limit its cell efficacy. These findings show the need to combine biochemical and physicochemical data when optimising HDAC inhibitors for triple-negative breast cancer.

Compounds 8o and 8p were identified as potent panHDAC inhibitors. They demonstrated cytotoxicity against triple-negative breast cancer cells. This provides a promising foundation for future structural optimization and preclinical development.

Globally rising incidences of pancreatic cancer, a leading cause of death, have made it imperative to explore new chemotherapeutic agents, such as ionic liquids (ILs), as an emerging class of anticancer agents. Nucleobase ionic liquids (NBILs) have shown great promise against pancreatic cancer PANC-1 cells. This study aims to synthesize purine and pyrimidine nucleobase ionic liquids (NBILs) and evaluate their in vitro anticancer activity on PANC-1 cells to gain valuable insights into the anticancer potential of NBILs.

Comprehensive in vitro studies, including flow cytometric apoptosis analysis, reverse transcription polymerase chain reaction (RT-PCR), gene expression studies, and molecular docking analysis, were performed to demonstrate the potent anticancer effects of NBILs.

A series of nucleobase ionic liquids (NBILs) was synthesized using a multi-step protocol. Significant anti-pancreatic cancer activity was observed for the synthesized NBILs against PANC-1 cells, with compound 14b showing high expression of CASP3 and a high percentage of apoptosis.

Molecular mechanism and in silico studies demonstrated remarkable anti-pancreatic cancer activity of NBILs via activation of CASP3 and regulation of the IRE1a pathway. The research highlights the future potential for utilizing NBILs against pancreatic cancer PANC-1 cells.

NBILs displayed significant anti-pancreatic cancer activity through apoptosis induction via activation of Caspase 3 and in silico regulation of the IRE1a pathway in pancreatic cancer PANC-1 cells.

The role of β-catenin signalling in the pathogenesis of Colorectal Cancer (CRC) is indisputable. In this study, we report the identification of a cytotoxic fraction that targets the β-catenin signalling axis in colorectal cancer cells.

Chromatographic and spectrometric techniques were used for the isolation and phytochemical characterization of Eudesmanolides (EDS). Cell-viability assays, flow cytometry, fluorescent microscopy, immunoblot analysis, qRT-PCR, and in silico molecular docking studies were used to analyse the antitumor potential of EDS against CRC cells. Toxicological evaluation of EDS was conducted in Swiss albino mice.

We have isolated and characterized the bioactive fraction designated EDS, consisting of the eudesmanolides, namely wedelolide D and prostrolide A, from the Ethyl Acetate (EA) leaf extract of the plant Sphagneticola trilobata (S. trilobata). EDS was found to be highly efficacious against CRC cells and induced an apoptotic mode of cell death in different CRC cell lines. Delineation of the apoptotic pathway induced by EDS revealed extrinsic pathway activation and amplification of the apoptotic signals via the intrinsic pathway through truncated-BID. Molecular investigations revealed EDS-mediated inhibition of β-catenin signalling and PPAR-γ (peroxisome proliferator-activated receptor gamma) activation in HCT116 CRC cells.

Our study revealed that EDS induced strong apoptotic signals in CRC cells, initiated at the cell surface, resulting in apoptosis involving extrinsic and intrinsic mechanisms irrespective of the p53 status or molecular phenotype of CRC cells. In addition, PPAR-γ activation by EDS resulted in the suppression of β-catenin nuclear accumulation and the subsequent inhibition of proliferative and survival signalling. Moreover, EDS was found to be pharmacologically safe.

To summarize, we demonstrate, with mechanism-based evidence, the chemotherapeutic efficacy of EDS, comprising the eudesmanolides, wedelolide D, and prostrolide A, derived from S. trilobata, against CRC. The potential of these lead-structures are worth exploring for their beneficial effects in combination with other therapeutic interventions.

Cancer is a multifactorial disease involving multiple interrelated molecular targets and signaling pathways. Some epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs could reduce the incidence of certain types of cancer, indicating the interplay between inflammation and cancer. Designing compounds that inhibit an enzyme of the arachidonic acid inflammatory cascade while exhibiting anticancer effects has emerged as a promising strategy.

A descriptive review and analysis of recently published studies on the synthesis of compounds that target two enzymes of the arachidonic acid cascade and simultaneously exhibit anticancer activity was performed.

Numerous cyclooxygenase-2 (COX-2) inhibitors with anticancer activity are known. Fewer examples exist for 5-lipoxygenase (5-LOX) inhibitors, while many dual COX-2/5-LOX inhibitors also display anticancer effects. Some examples of dual inhibitors with anticancer potential include 5-LOX/microsomal prostaglandin E2 synthase (mPGES), and COX-2/soluble epoxide hydrolase inhibitors. There are also compounds designed to inhibit three targets: COX-2, 15-LOX, and carbonic anhydrase.

Given the complex interplay between inflammation and cancer, the term “anticancer effects” encompasses various therapeutic opportunities, ranging from adjuvant therapy and chemoprevention to angiogenic and cytotoxic activity.

This multitarget approach highlights the broad therapeutic possibilities of targeting inflammatory pathways, establishing a direction for the development of innovative anticancer therapies with improved safety profiles.

Poly(2-ethyl-2-oxazoline) (POx) has emerged as a highly promising drug delivery polymer due to its biocompatibility, stealth-like behavior, and versatile functionalization options. POx-based nanocarriers offer significant advantages for targeted drug delivery in oncology, particularly for challenging tumors such as triple-negative breast cancer (TNBC).

Recent literature from 2015 to 2025 on the synthesis, characterization, and biological applications of POx-based nanocarriers was systematically reviewed. Emphasis was placed on drug conjugation techniques, in vitro and in vivo performance, and computational studies that inform design optimization.

POx micelles and hybrid systems demonstrate improved encapsulation efficiency, reduced off-target toxicity, and sustained drug release, achieving effective tumor targeting via the enhanced permeability and retention (EPR) effect. Notably, POx micelles loaded with β-elemene exhibit dual pH/GSH-responsive behavior with >92% encapsulation efficiency. Computational modeling has guided micelle design and predicted critical drug–polymer interactions.

The structural flexibility of POx enables the engineering of dual-drug carriers and theranostic platforms. Clinical translation is progressing, although challenges remain regarding large-scale synthesis and regulatory standardization. Integration of POx-based systems into combination therapies and personalized oncology strategies represents a promising path forward, supported by encouraging preclinical results.

POx nanocarriers exhibit strong translational potential for TNBC due to high drug loading, biocompatibility, and tunable release profiles. They provide enhanced tumor accumulation, active targeting, and the ability to overcome multidrug resistance, supported by favorable pharmacokinetics and computational design insights. Remaining challenges include large-scale production, long-term safety assessment, and regulatory approval. Future directions focus on dual- and stimuli-responsive systems and their integration into precision oncology to accelerate clinical translation.

Prostate cancer remains the second most common cancer among men around the world, with 1.4 million new cases annually. Treatment resistance and off-target toxicity require innovative therapeutic approaches. Natural compounds such as eugenol exhibit anticancer potential, but poor pharmacokinetic properties constrain clinical application.

This study evaluated the cytotoxic, apoptotic, and pharmacokinetic properties of three eugenol-derived allyl phenol compounds (38, 42, 47), previously recognized as potent 15-lipoxygenase-1 (15-LOX-1) inhibitors, in prostate cancer models.

The cytotoxic activity was evaluated in PC-3 prostate cancer cells and Human Dermal Fibroblasts (HDF) using AlamarBlue assays, flow cytometry, and morphological analysis. Computational validation involved Density Functional Theory (DFT) calculations, molecular docking into 15-lipoxygenase-1 (15-LOX-1; PDB: 2P0M), and structural analysis. Pharmacokinetic and toxicity profiles were predicted in silico using SwissADME, pkCSM, and ProTox-III platforms.

All three compounds were cytotoxic to PC-3 cells in a concentration-dependent way with some selectivity for normal cells. Apoptosis was confirmed by increased sub-G1 peak and morphological changes, while BAX or BCL-2 mRNA levels did not change. In silico studies (DFT and docking) showed that the compounds bound well to 15-LOX-1 (docking scores: -6.6 to -7.3 kcal/mol), with compound 42 having the strongest binding affinity. Structural analysis showed that the proteins were moderately flexible (B-factor: 47.45 ± 13.07 Ų), which supports stable ligand accommodation. Computational ADME/toxicity predictions suggested generally favorable pharmacokinetic profiles; however, compound 42 was poorly soluble, and compound 47 was identified as a P-gp substrate, indicating a potential efflux liability.

The pro-apoptotic effects observed despite unaltered BAX and BCL-2 mRNA levels indicate that the apoptotic response is likely mediated through mechanisms other than transcriptional regulation of these genes, potentially by blocking 15-LOX-1. Computational modeling indicated that all three compounds can effectively bind to the 15-LOX-1 active site, and their binding affinities are in line with their experimental inhibitory potencies (IC50: 0.80–0.88 µM). The integration of in vitro and in silico results confirms the therapeutic potential of these compounds and underscores the necessity for additional mechanistic studies and in vivo evaluation.

These results highlight the anticancer properties of eugenol-derived allylphenol compounds. The compounds induce apoptosis by mechanisms independent of BAX/BCL-2 transcriptional modulation. Computational modeling suggests potential involvement of 15-LOX-1; nevertheless, direct mechanistic validation via caspase activity, ROS generation, or protein-level quantification of BAX/BCL-2 is necessary to verify the apoptotic pathway. The compounds suggest favorable pharmacokinetic profiles along with strong enzyme binding characteristics. Compound 38 exhibited the most balanced profile, characterized by high cytotoxicity, selectivity, and predicted ADME properties. Additional mechanistic investigations and in vivo validation are necessary to advance these candidates through preclinical development.

Predicting prognosis in cancer is complex. While traditional staging methods are useful, they do not fully account for the unique biology of each tumor. There is a growing need for biomarkers that capture this biological nuance, which is where molecular signatures like those involved in lactate metabolism (LMRGs) come into play.

We conducted a structured narrative review of existing studies to investigate the link between LMRGs and patient survival. Our analysis spanned a wide array of cancers, from common types like breast and lung cancer to rarer forms such as sarcomas and gliomas, employing relevant keywords associated with lactate metabolism, gene signatures, and cancer prognosis.

Our synthesis of the data suggests a consistent trend: higher activity of lactate metabolism genes may be associated with more aggressive disease. Across many different cancers, this signature was reliably associated with worse outcomes for patients, including shorter survival times.

These findings suggest that LMRGs could be a valuable tool for dividing patients into more precise risk groups, potentially leading to more personalized treatment plans. However, moving this from research to the clinic will require overcoming hurdles like standardizing tests and proving its value in clinical trials.

In summary, lactate metabolism genes may hold promise as a broadly applicable warning sign for aggressive cancer. Tapping into this metabolic “switch” could ultimately help doctors better predict outcomes and tailor treatments for their patients.