Curvularins, a class of macrocyclic lactones, have cytotoxic, antimicrobial, and anti-inflammatory properties. Curvularin, a 12-membered macrolactone, was used as a scaffold to design and synthesize structurally modified analogues to investigate structure-activity relationships and improve biological efficacy. Three series of curvularin-based analogues, Cur-5H-OMe, Cur-4P-OMe, and Cur-OMe, were synthesized with the same core structure but different substituent sizes and positions. Nine representative derivatives were evaluated for anti-inflammatory, anticancer, antibacterial, and antifungal activities. In LPS-stimulated RAW 264.7 macrophages, most compounds inhibited nitric oxide (NO) production in a concentration-dependent manner but exhibited cytotoxicity at high concentrations. Cytotoxicity assays against HaCaT cells and human cancer cell lines (HCT116, HeLa, and A375) revealed limited selectivity toward cancer cells. Antimicrobial evaluation indicated selective activity against the Gram-positive bacteria, Staphylococcus aureus. Compound 23 exhibited superior antibacterial potency compared with kanamycin and notable antifungal activity against Candida albicans. This study provides a versatile synthetic platform and identifies key structural features of curvularin derivatives, demonstrating their potential as anti-inflammatory and antimicrobial lead compounds.

According to the World Health Organization, antibiotic research remains insufficient, emphasizing the urgent need for new active molecules, particularly against resistant bacteria. Based on known antibacterial scaffolds, new fluoroquinolone derivatives have been synthesized by our research group, including compound 7a, a difluoroboranyl-fluoroquinolone that previously demonstrated activity against sensitive strains.

Dysregulated angiogenesis is involved in cancer and numerous ischemic, autoimmune and inflammatory diseases, prompting extensive research that has yielded a growing array of angiogenesis-modulating molecules used in clinical practice. The dietary phytocomplex of Cruciferous vegetables exhibits multiple biological activities in both in vitro and in vivo models. However, the impact of a myrosinase-activated broccoli extract (MaBE) on angiogenesis, as well as on stromal-endothelial interactions governing endothelial cell behavior, has not yet been explored. We investigated the effects of MaBE on endothelial-stromal crosstalk using endothelial cells (HUVECs) and fibroblasts (HFF1) both individually and in a fibroblast-conditioned medium model. MaBE dose-dependently inhibited endothelial viability, migration and tube formation, key steps of angiogenesis, through interference with the VEGF-VEGFR2 axis. Notably, MaBE also markedly suppressed HFF1-driven HUVEC migration and capillary-like structure formation, likely through the inhibition of fibroblast motility and the downregulation of VEGF and angiogenin signaling in HFF1 cells. Overall, these findings provide new insight into MaBE regulation of pro-angiogenic behaviors in both endothelial cells and fibroblasts while disrupting their functional interplay. By targeting multiple cellular compartments and key mediators involved in angiogenesis, MaBE emerges as a promising bioactive extract with potential relevance for the management of pathological angiogenesis-related disorders.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality in the world. Although there is an armamentarium of therapeutic options available for HCC therapy, current treatment modalities still face challenges, such as limited effectiveness and resistance to therapy due to inherent intratumoral heterogeneity. Hence, the development of novel therapeutics is an unmet need. Microalgae possess the ability to provide naturally derived compounds that are attractive for biomedical applications. The multifunctional nature of microalgae, with its unique combination of anticancer metabolites, oxygen-generating capability, and photosensitizing activity, make them a versatile platform for developing next-generation cancer therapeutics. In light of the above, this succinct narrative review highlights the potential biomedical applications of microalgae in cancer therapy, with a focus on HCC. Preclinical studies have shown the significant potential of microalgae as naturally occurring sources of chemopreventive and anticancer agents against HCC. Future directions include the use of biotechnology to enhance the production of microalgal-derived bioactive compounds and the formulation of biocompatible and biodegradable drug-microalgae embolic agents with prolonged release of anticancer drugs, thereby giving rise to synergistic antitumor effects, and their application for the delivery of immune checkpoint inhibitors for immunotherapy in HCC. Overall, microalgae hold considerable promise for advancing innovative therapeutic strategies against HCC.

Bessera elegans (Asparagaceae) is an endemic Mexican species that is traditionally valued for ornamental purposes and locally reported medicinal uses, yet it remains largely underexplored from phytochemical and biological perspectives. The identification of bioactive secondary metabolites from under-investigated plant species is a key step toward developing plant-derived compounds with potential biotechnological applications. Therefore, in this context, we compile and critically analyze the available information on the botany, phytochemistry, and reported cytotoxic and insecticidal activities of B. elegans. Phytochemical studies, mainly focused on the bulbs, have led to the isolation of steroidal glycosides, homoisoflavonoids, flavonoids, and norlignans. Several of these compounds exhibit cytotoxicity against human cancer cell lines, including leukemia and lung adenocarcinoma models. More recent investigations of flower extracts have revealed additional classes of secondary metabolites and preliminary insecticidal activity, highlighting the species' chemical diversity. Although the current biological evidence remains limited, the reported cytotoxic and insecticidal effects provide a biochemical basis supporting the relevance of B. elegans as a potential source of plant-derived bioactive compounds. This review highlights existing knowledge gaps and emphasizes the need for further phytochemical and biological studies to support future biotechnological applications of metabolites from underexplored endemic plant species.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds-sesquiterpene lactones (achillin and polymatin A) and naphthoquinones (α, β-lapachone and lapachol)-in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC50 values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. The naphtoquinones α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC50 of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure-activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research.

Three new Mn(II) complexes with imidazo[1,2-a]pyridine derivatives were synthesized and structurally characterized in a solid state by single crystal X-ray diffraction, FT-IR and Raman spectroscopy, and thermal analyses. The investigated compounds include [Mn(3-Climpy)2Cl2(MeOH)2] (1), [Mn(3-Brimpy)2Cl2(MeOH)2] (2), and a rare double chloro-bridged coordination polymer [Mn(impy)2Cl2]n (3). Spectroscopic studies were used to assess their potential stability in DMEM (Dulbecco's Modified Eagle Medium), and encapsulation in Pluronic P-123 micelles improved their solubility in aqueous solution, as well as cellular uptake and selectivity. Biological evaluation revealed negligible cytotoxicity against most cancer and control cell lines, but unexpectedly high activity against pancreatic adenocarcinoma (PANC-1), exceeding that of cisplatin. Complex 2, bearing a bromine substituent in the imidazole ring, showed the strongest effects, correlating with enhanced intracellular accumulation, reactive oxygen species (ROS) generation, and mitochondrial membrane potential disruption. Molecular docking and protein binding assays demonstrated moderate affinity toward human serum albumin (HSA) and transferrin, whereas DNA interaction was weak and non-damaging. These results highlight the structure-activity relationship of Mn(II) imidazo[1,2-a]pyridine complexes and support their potential as targeted redox-active agents against pancreatic cancer, with polymeric encapsulation providing an effective strategy to enhance biological performance.

The design, production, and study of new poly[ADP-ribose] polymerase 1 (PARP-1) inhibitors have emerged as an interesting exploration area, since PARP-1 is an overexpressed enzyme in several carcinomas. In this sense, menadione, or vitamin K3, is well known for its use in correct blood clotting, and for the generation of reactive oxygen species, but it is important to mention that it has been used as an antineoplastic agent against several cell lines. Related to the last commentary, in this work, four novel molecules (2-5) were produced from menadione through a Michael addition protocol, using 1,2-ethanedithiol, cysteamine, benzene-1,4-dithiol, and 4-aminobenzenethiol as nucleophiles, and menadione (1) as substrate, to evaluate them as plausible candidates to inhibit PARP-1. It is convenient to note that after their production and spectroscopic characterization, both docking and theoretical studies for each compound were conducted, using density functional theory (DFT) with the hybrid method B3LYP with the 6-311G(d,p) basis set. As a complement, the reactivity properties determined by DFT calculations were obtained for all compounds; the results revealed that 2 has the best properties to bind with PARP-1, and 3 offered good results. Hence, the target compounds were evaluated in vitro, determining their activity against PARP-1, using olaparib as a reference. Molecules 2 and 3 displayed the free binding energy values -7.97 and -9.35 kcal/mol, respectively, but 2 has the best IC50 value, 13.76 µM. It is important to highlight that 2 and 3 must be considered as potential new inhibitor agents against PARP-1, exhibiting competitive IC50 values with olaparib.

Breast cancer represents a persistent global health burden, marked by extensive molecular heterogeneity and frequent therapeutic resistance in aggressive subtypes, particularly triple-negative breast cancer (TNBC). These clinical challenges underscore the urgency for alternative therapeutic strategies. Bioactive alkaloids isolated from Nelumbo nucifera, especially the bisbenzylisoquinoline compounds liensinine (LIE), isoliensinine (ISO), and neferine (NEF), have emerged as promising candidates due to their ability to disrupt oncogenic signaling pathways and inhibit malignant cellular transformation. The present study conducted a systematic investigation of LIE, ISO, and NEF across multiple breast cancer cell lines, including highly aggressive TNBC models. Results revealed potent growth-inhibitory effects mediated through apoptosis induction and cell cycle arrest at both the G1 and G2/M phases. Furthermore, transcriptomic profiling and molecular analysis identified LIE as a principal effector, driving extensive transcriptional reprogramming and targeting the MAPK and mTOR pathways as core regulators of its anti-cancer efficacy. Collectively, these findings define a mechanistic framework for the anti-cancer potential of N. nucifera-derived alkaloids and provide a compelling foundation for their development as therapeutic candidates for advanced breast cancer.

Studies of natural products and their semisynthetic derivatives are a valuable source of therapeutic agents. The aim of this work was to obtain new 30-phosphoramidate derivatives of betulin and determine their biological potential. The synthetic approach utilized the Staudinger reaction (the introduction of a phosphoramidate group), the Steglich reaction (the introduction of an alkynyl group), and the Jones reaction (the introduction of a carboxyl group). The structures of the target compounds were determined using spectroscopic methods (1H NMR, 13C NMR, 31P NMR, and HRMS). The new derivatives were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, and HCT116 cancer cells and against normal MCF-10A cells using the MTT and SRB methods. Apoptosis studies were performed for the most active compounds (6B and 7A), potential molecular targets (AutoDock software) were identified, and lipophilicity parameters (RP-TLC method, SwissADME website) were determined. The greatest effect on apoptosis and caspase 3/7 activation was observed for the diester derivative 7A. Compound 7A showed a high lipophilicity parameter in the study group.

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC50 = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC50 = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC50 = 0.102 ± 0.005 µM) and CA XII (IC50 = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G2/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms.

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. Methods: A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including CYP2D6, CYP3A4/5, UGT1A4, UGT2B7/15, SULT1A1/2, and SULT1E1, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. Results: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with SULT1A1 copy number variation (p = 0.030) and SULT1E1 rs3736599 (p = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with UGT2B7 rs7439366 (p = 0.040) and CYP3A4 rs2242480 (p = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to SULT1A2*2 (p = 0.050), SULT1E1 rs3736599 (p = 0.016), and UGT2B15 rs4148269 (p = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. Conclusions: This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy.

Copper-organic compounds are being investigated as antitumor candidates. Besides their efficacy as cytotoxic agents alone, the oxidative potential of electrochemical Cu2+-to-Cu1+ transition emerges as an attractive approach for elimination of tumor cells otherwise resistant to chemotherapy. To minimize side effects of the potent oxidative burst upon Cu(II) reduction, the metal cations should be delivered to the tumor site. Taking advantage of the ability of bisphosphonates to accumulate in the bone, we synthesized a Cu(II) complex of zoledronic acid (ZA), an FDA-approved drug for prevention of bone destruction. The CuZA complex obtained upon precipitation of ZA and different copper salts (sulfate, chloride or perchlorate) were structurally identical, consisting of two organic moieties coordinated by three metal cations. Combined treatment with water-soluble formulations of CuZA and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of CuZA and cysteine alone. Importantly, the K562 chronic myelogenous leukemia cells that demonstrated an attenuated response to the 3d generation Bcr-Abl tyrosine kinase inhibitor in the medium conditioned by bone marrow-derived fibroblasts, were readily killed by CuZA-cysteine combination. Thus, oxidative burst upon metal reduction in CuZA complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment.

Heat-shock factor 1 (HSF1) is a multifunctional transcription factor whose overexpression is associated with the development, progression, and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). In the present study, we thoroughly investigated the antitumor activity of NXP800, a recently developed HSF1 inhibitor that is currently tested in clinical trials, on HCC growth. We discovered that NXP800 inhibits the cell growth of human HCC cell lines by reducing proliferation, inducing apoptosis, and causing DNA damage. At the metabolic level, NXP800 significantly decreased mitochondrial respiration, which was associated with extensive structural alterations in the mitochondria, and reduced glycolysis of HCC cells. At the molecular level, NXP800 administration led to the upregulation of the integrated stress response and downregulation of the E2F1 signaling cascade. In addition, NXP800 profoundly constrained the growth of HCC patient-derived organoids. Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC.

Glioblastoma is the most aggressive primary malignant tumor of the central nervous system in adults, with a poor prognosis and high resistance to conventional therapies. Platinum drugs like cisplatin are effective but limited by systemic toxicity, poor blood-brain barrier penetration, and resistance. Natural compounds are increasingly studied for their anticancer potential and ability to enhance existing therapies. Based on this rationale, we designed Pt(IV)Ac-GA, a novel platinum(IV) complex obtained by conjugating cisplatin with ganoderic acid A, a triterpenoid from Ganoderma lucidum known for anticancer and immunomodulatory effects. The compound was synthesized, structurally characterized, and showed high stability and favorable pharmacokinetics. In vitro, Pt(IV)Ac-GA strongly reduced the viability of U251 and T98G glioblastoma cells while sparing normal astrocytes. It triggered apoptosis, cell cycle arrest, impaired migration, and increased sensitivity to ferroptosis and mitochondrial dysfunction. These results highlight Pt(IV)Ac-GA as a promising candidate to overcome current limitations in glioblastoma treatment.

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC50 values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC.

Chalcones are compounds containing an α,β-unsaturated carbonyl group that have been studied due to their structural simplicity, ease of synthesis, and broad spectrum of biological activities. Within this family, nitrochalcones have gained relevance due to the influence of the nitro group (-NO2) on the modulation of their electronic properties, chemical reactivity, and pharmacological behavior. This review presents a critical analysis of advances in the biological activities and possible mechanisms of action of nitrochalcones and their derivatives, with an emphasis on their structure-activity relationships and therapeutic potential. The available evidence shows that nitrochalcones and their derivatives act as multitarget molecules, capable of intervening in key biological processes such as oxidative stress, mitochondrial dysfunction, inflammation, and cell signaling pathways associated with proliferation and apoptosis. Several studies report anticancer, anti-inflammatory, antiparasitic, antimicrobial, antifungal, and cardiovascular activities, often with favorable selectivity toward pathological cells over healthy cells.

Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer deaths, with resistance to targeted therapies posing a major clinical challenge. Drug-tolerant persister (DTP) cells are key contributors to resistance, and targeting them offers new strategies to enhance existing treatments. MicroRNAs (miRNAs), particularly the tumour-suppressive miR-15/107 family, offer promise due to their ability to target multiple oncogenic pathways. This study evaluated a synthetic consensus miRNA mimic, conmiR-15/107, in NSCLC cell line models. Dose-response assays showed robust, dose-dependent growth inhibition in both EGFR-mutant (PC9) and KRAS-mutant (H358 and A549) lung adenocarcinoma cells, but not in the human bronchial epithelial cell line BEAS-2B. When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells. RT-qPCR confirmed downregulation of conmiR-15/107 targets, including MEK1, BCL2 and BRCA1, suggesting a multi-target mechanism of action. Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced hepatocellular carcinoma (HCC), establishing immunotherapy-based combinations as the standard of care. Improved treatment responses have expanded liver transplant eligibility for selected patients with advanced HCC through downstaging or bridging strategies. Such advances have directly influenced transplant candidacy and post-transplant outcomes. However, accumulating evidence indicates that pretransplant exposure to ICIs may disrupt post-transplant immune homeostasis, increasing the risk of acute allograft rejection and graft failure requiring retransplantation. From an immunological perspective, rejection following pretransplant ICI therapy predominantly manifests as T cell-mediated rejection and is characterized by the sustained activation of effector T cells and impairment of regulatory immune pathways. Blockade of immune checkpoint signaling interferes with mechanisms critical for allograft tolerance, including T cell apoptosis and regulatory T cell induction. Recent studies further underscore the importance of the washout period between ICI discontinuation and LT, with longer washout intervals being associated with lower rejection rates. Importantly, timely recognition and appropriate immunosuppressive management can often resolve acute rejection without adversely affecting long-term graft outcomes. This review integrates current immunological insights with emerging clinical evidence to inform optimal transplant timing and management strategies for liver transplant candidates receiving ICIs.

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in models of triple-negative breast cancer (TNBC). In vitro screens conducted in two TNBC cell lines nominated ABCG2 as the top resistance-conferring gene in both models. Validation studies assessing clonogenic survival and apoptosis confirmed that ABCG2 overexpression enhanced TNBC resistance to 2257 in vitro, while knockdown enhanced sensitivity. These findings suggest that 2257 is a substrate of ABCG2's drug efflux activity. However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics.