Search Results (653)

Carmustine (BCNU) is a powerful alkylating agent primarily used in the chemotherapeutic treatment of malignant brain tumors. However, its clinical application faces significant constraints due to its lipophilicity, low thermal stability, and rapid degradation in physiological environments. To tackle these challenges, our research aimed at the development and detailed characterization of α-cyclodextrin (α-CD) inclusion complexes (ICs) with BCNU employing three different synthesis techniques: co-grinding, cryomilling, and co-precipitation. The selected synthetic methods displayed variations dependent on the technique used, affecting the efficiency, inclusion ratios, and drug-loading capacities, with co-precipitation achieving the most favorable complexation parameters. Structural elucidation through ¹H NMR chemical shifts analysis indicated that only partial inclusion of BCNU occurred within α-CD in ICs produced via co-grinding, while cryomilling and co-precipitation allowed for complete inclusion. Multimodal spectroscopic analyses (FT-IR, UV-Vis, ¹³C CP MAS NMR, and ESI-MS) further substantiated the effective encapsulation of BCNU within α-CD, and systematic solubility assessments via Job’s continuous variation and the Benesi-Hildebrand method revealed a 1:1 host-guest stoichiometry. The ICs obtained were evaluated for BCNU release in vitro at pH levels of 4, 5, 6.5, and 7.4. The mechanism of BCNU drug release was determined to be Fickian diffusion, with the highest cumulative release noted in the acidic microenvironment. These findings collectively validate the effectiveness of α-CD as a functional excipient for the modulation of BCNU’s physicochemical properties through non-covalent complexation. This strategy shows potential for increasing the stability and solubility of BCNU, which may enhance its therapeutic effectiveness in the treatment of brain tumors. Full article

The development of metallopharmaceuticals for diabetes treatment has garnered increasing attention due to its insulin-mimetic properties, particularly in vanadium complexes. In this study, we report the biophysical evaluation of a series of 3-hydroxy-4-pyridinone (3,4-HPO) vanadium complexes, designed to improve lipophilicity and biological cytocompatibility. Dynamic light scattering (DLS) was used to get insight on the size of the liposomes and Differential Scanning Calorimetry (DSC) was employed to investigate the interaction of these complexes with model biological membranes made from dimyristoylphosphatidylcholine (DMPC) unilamellar liposomes. The thermotropic phase behavior of the lipid bilayers was analyzed in the presence of vanadium complexes. The results reveal that the alkyl chain length of the 3,4-HPO ligands modulates membrane interaction of the respective vanadium compounds, with specific complexes inducing significant shifts in the lipid phase transition temperature (T_m), suggesting alterations in membrane fluidity and packing. These findings provide valuable insight into the membrane affinity of vanadium-based drug candidates and support their potential as next-generation antidiabetic agents. Full article

Fanconi anemia (FA) is a rare bone marrow failure disorder characterized at the cellular level by hypersensitivity to alkylating agents, such as diepoxybutane (DEB), and redox imbalance. Alterations in red blood cells (RBCs), which play a key role in systemic antioxidant defense, are among the earliest changes in FA, consistent with an oxidative stress (OS) profile. Previous studies about antioxidant activity in RBCs from these patients are scarce and inconsistent. This study aimed to better understand the antioxidant profile in RBCs from FA patients carrying the homozygous FANCA c.295C>T variant. Glutathione content and the activities of catalase, superoxide dismutase, glutathione peroxidase (GPx), and Pi-class glutathione S-transferase (GSTP1) were quantified, both at baseline and after culture with and without DEB, in RBCs from FA patients, FA carriers, and controls. At baseline, FA RBCs displayed significantly reduced catalase activity, whereas GPx and GSTP1 activities were significantly increased, suggesting an OS preconditioning state, not observed in RBCs from FA carriers and controls. Under culture and DEB exposure, FA RBCs exhibited a significant decline in both GSTP1 and GPx activities, contrary to controls. These new findings highlight a key role of GSTP1 and GPx activities in baseline antioxidant defense, severely compromised in case of increased OS toxicity. Full article

Compound T1089—a novel nitrogen mustard based on an indole-3-carboxylic acid derivative (ICAD)—has been synthesized. The ICAD used as the basis for T1089 is a TLR agonist capable of activating an antitumor immune response. This study describes the synthesis method and presents the results of preliminary investigations of this compound. This research included an assessment of acute toxicity in mice, in vivo clastogenic activity evaluated via the bone marrow chromosome aberration (BMCA) test in mice, in vitro cytotoxicity determined by the MTT assay against human lung carcinoma A549 cells, and in vivo antitumor effects (ATEs) in models of conventional chemotherapy (CCT) of solid tumors in mice. The bifunctional alkylating agent cyclophosphamide (CPA) was used as a reference drug. Toxicological studies revealed that T1089 belongs to toxicity class III (moderately toxic), with acute toxicity values (LD₁₆ and LD₅₀) in mice following intraperitoneal (i.p.) administration being 191 and 202 mg/kg, respectively. The alkylating activity and clastogenic potential of T1089 were demonstrated by its effects in the BMCA test, which were comparable to those of CPA. A single i.p. administration of CPA and T1089 at a dose of 0.064 mmol/kg induced similar stimulation of structural mutagenesis associated with DNA strand breaks. The frequency of karyocytes with aberrations increased 20-fold compared to the control, primarily due to a rise in chromatid breaks and fragments, and to a lesser extent, due to an increase in exchange-type aberrations. In vitro cytotoxicity studies indicated differences in the mechanisms of alkylating activity between CPA and T1089. According to the MTT assay, the cytotoxic effects of CPA were observed only at concentrations exceeding 2 mM (IC₅₀ = 4.2 ± 0.3 mM), corresponding to lethal in vivo doses, which is expected since the formation of CPA’s alkylating metabolite requires hepatic microsomal enzymes. In contrast, significant cytotoxic effects of T1089 were observed at much lower concentrations (15–50 μM, IC₅₀ = 33.4 ± 1.3 μM), corresponding to safe in vivo doses. Differences were also observed in the in vivo ATEs of CPA and T1089 in the Ehrlich solid carcinoma (ESC) CCT model. Following seven i.p. administrations at 48 h intervals (33 mg/kg), both compounds exhibited increasing toxicity, manifested as cumulative body weight loss in treated mice. However, despite the aggressive CCT regimen, ESC showed low sensitivity to CPA. The ATE of CPA developed slowly, reaching a significant level only after four injections, and even after seven administrations, tumor inhibition (TI) did not exceed 30%. In contrast, ESC was significantly more sensitive to T1089 under the same CCT conditions. The ATE of T1089 exhibited a cumulative pattern but developed more rapidly and to a greater extent. A significant antitumor effect was observed after just two injections, with maximal efficacy (TI = 53%) achieved after four injections and sustained until the end of the observation period. A high ATE of T1089 was also observed in the B-16 melanoma CCT model. Following six i.p. administrations at 48 h intervals (28 mg/kg), T1089 treatment was associated with minimal toxicity. Despite this mild CCT regimen, melanoma exhibited high sensitivity to T1089. Maximal ATE (TI = 56%) was achieved after two injections, and subsequent administrations maintained a consistently high efficacy (TI = 52–55%) until the end of the study. In summary, preliminary findings demonstrate that T1089 possesses alkylating activity characteristic of bifunctional agents, accompanied by high in vitro cytotoxicity and in vivo ATEs in CCT models (at high doses). Given that the ICAD used as the basis for T1089 is a TLR agonist capable of stimulating antitumor immunity, T1089 can be considered a dual-action alkylating agent with combined antitumor effects. These results justify further investigation of T1089 in conventional and metronomic chemotherapy regimens, particularly in combination with immune checkpoint inhibitors and antitumor vaccines. Full article

Background/Objectives: Soft tissue sarcomas are rare, heterogeneous tumors with limited therapeutic options and suboptimal outcomes in advanced stages. Lurbinectedin is a promising new antineoplastic alkylating agent. This study investigates its cytotoxic effects and its potential as a radiosensitizing agent on soft tissue sarcoma. Methods: Four soft tissue sarcoma cell lines were treated with lurbinectedin alone or in combination with ionizing radiation. Single-dose irradiation in a 4-day protocol was compared with prolonged treatment and an additional fractionated ionizing radiation scheme in a 6-day protocol. Cellular responses were analyzed by flow cytometry for apoptosis (Annexin V)/necrosis (7AAD) and cell cycle (Hoechst), clonogenic cell survival, and scratch assays for cell migration. Results: In the 4-day protocol, lurbinectedin induced G2/M arrest in all cell lines (p = 0.029) and significantly increased apoptosis/necrosis (p = 0.029) in SW-872. Lurbinectedin-treatment resulted in a decrease (p ≤ 0.002) of clonogenic cells in all cell lines. In the scratch assay, cell migration was delayed in two cell lines (p = 0.048) after lurbinectedin-treatment. Additional radiotherapy had no significant effect compared to lurbinectedin-monotherapy in apoptosis/necrosis and G/2M arrest in the 4-day protocol, clonogenic cell assay, and scratch assay. In the 6-day protocol, lurbinectedin induced an increase (p = 0.029) in G2/M arrest in all cell lines and apoptosis/necrosis in three cell lines, while resulting in a decrease (p < 0.001) of clonogenic cells. Additional radiotherapy had a significant effect on the decrease in clonogenic cells (p ≤ 0.048) in two cell lines but did not increase G2/M arrest and apoptosis/necrosis. Conclusions: Lurbinectedin had strong effects on three of the selected cell lines by inducing G2/M arrest, promoting apoptosis/necrosis, and reducing clonogenic survival, suggesting that it may be a promising chemotherapeutic agent in soft tissue sarcoma treatment. The effect on the fourth cell line was limited, as well as the effect on cell migration. Single-dose irradiation occasionally interfered with the effects of Lurbinectedin, whereas adding fractionated irradiation caused an additional decrease in clonogenic survival, indicating that the combination of Lurbinectedin with fractionated ionizing radiation may have promising effects. Full article

Metastasis is the main cause of failure in anticancer therapies, and is frequently related to poor prognosis for patients. The true challenge in extending cancer patient life expectancy, eventually managing cancer as a chronic disease with periodic but controllable relapses, relies on the development of effective therapeutic strategies specifically targeting key mechanisms involved in the metastatic cascade. Traditional chemotherapy with alkylating agents, microtubule inhibitors, and antimetabolites has shown limited efficacy against metastatic cells, largely due to the emergence of chemoresistant populations that undergo epithelial-to-mesenchymal transition (EMT), promoting the colonization of distant organs and sustaining metastatic progression. This scenario has spurred significant efforts to identify small molecules and biologics capable of interfering with specific steps in the metastatic process. In this review, we provide an overview of recent advances involving small interfering RNAs (siRNAs) and microRNAs (miRNAs) in cancer therapy. Although most of these agents are still under investigation and have not yet been approved for clinical use, insights into their development stage offer valuable information to identify new targets in the ongoing fight against metastasis. Particular emphasis is placed on the role of chemical modifications applied to siRNAs, such as backbone, sugar, terminal, base, and conjugation changes, and how these factors influence their stability, immunogenicity, and targeting precision. By integrating these aspects into the discussion, this review provides a focused and up-to-date resource for researchers in medicinal chemistry, drug delivery, and pharmaceutical formulation, where molecular design plays a critical role in therapeutic success. Full article

The continuous increase in microbial resistance to therapeutic agents has become one of the greatest challenges to global health. In this context, the present study investigated the bioactivity of 25 chroman-4-one and homoisoflavonoid derivatives—17 of which are novel—against pathogenic microorganisms, including Staphylococcus epidermidis, Pseudomonas aeruginosa, Salmonella enteritidis, Candida albicans, C. tropicalis, Nakaseomyces glabratus (formerly C. glabrata), Aspergillus flavus, and Penicillium citrinum. Antimicrobial assay was performed using the microdilution technique in 96-well microplates to determine the minimum inhibitory concentration (MIC). Thirteen compounds exhibited antimicrobial activity, with compounds 1, 2, and 21 demonstrating greater potency than the positive control, especially against Candida species. Molecular modeling suggested distinct mechanisms of action in Candida albicans: 1 potentially inhibits cysteine synthase, while 2 and 21 possibly target HOG1 kinase and FBA1, key proteins in fungal virulence and survival. Our findings indicated that the addition of alkyl or aryl carbon chains at the hydroxyl group at position 7 reduces antimicrobial activity, whereas the presence of methoxy substituents at the meta position of ring B in homoisoflavonoids enhances bioactivity. These findings highlight key structural features of these compound classes, which may aid in the development of new bioactive agents against pathogenic microorganisms. Full article

Obesity is a major global health concern associated with increased risks of chronic diseases and mortality. Inhibiting pancreatic lipase, a key enzyme in dietary fat absorption, presents a promising therapeutic approach. This study aimed to evaluate the inhibitory potential of piperidine derivatives (1 and 2) and pyrrolidine derivatives (3–13) against pancreatic lipase (PL) through both enzymatic assays and molecular docking simulations. Among the tested compounds, compound 12 demonstrated the highest PL inhibitory activity with IC₅₀ 0.143 ± 0.001 mg/mL and the strongest binding energy (−8.24 kcal/mol), attributed to extensive hydrogen bonding with Gly76, Phe77, Asp79, and His151. Compounds 10 and 13 also exhibited notable inhibitory activity, attributed to their extensive hydrogen bond network with residues Gly76, Phe77, Asp79, and His151. Particularly the presence and position of hydroxy and carbonyl groups and the length of alkyl side chains critically influenced binding stability and specificity. These findings demonstrate that specific structural modifications in pyrrolidine derivatives significantly affect pancreatic lipase inhibition. Compound 12, with its optimal molecular architecture and interaction profile, stands out as the most promising candidate for further development as an anti-obesity agent, with compounds 10 and 13 offering additional scaffolds for future optimization. Full article

Background: The increasing prevalence of antibiotic-resistant bacterial strains highlights the urgent need for new membrane-targeting antimicrobial agents. Bisquaternary ammonium compounds (bisQACs) have attracted attention for their ability to disrupt bacterial membranes more effectively than monoquaternary analogs. Quinuclidine, known for its health-beneficial properties, has previously been explored for monoQAC derivatization, but studies using natural scaffolds to generate bisQACs remain limited. Methods: Here, we synthesized twelve novel quinuclidine-based bisQACs, systematically varying alkyl chain and linker lengths to investigate structure–activity relationships. Results: Several compounds, including 2(QC₁₆)₃, 2(QC₁₆)₄, 2(QC₁₄)₆, and 2(QC₁₆)₆, exhibited strong activity against Staphylococcus aureus (including MRSA), Listeria monocytogenes, and Escherichia coli, with 2(QC₁₆)₆ being the most potent (MICs 5–38 µM). While cytotoxicity was observed on human RPE1 and HEK293 cells, selectivity indices indicated a favorable therapeutic window relative to reference QACs. Conclusions: These compounds also inhibited biofilm formation and induced rapid bacterial killing through a membrane-disruptive mode of action. Molecular docking showed that alkyl chain and linker variations modulate binding to the QacR efflux regulator, revealing a lower potential for efflux-mediated resistance. Overall, quinuclidine-based bisQACs represent promising leads for potent, selectively active next-generation antimicrobials with a reduced likelihood of resistance development. Full article

Background/Objectives: The conventional treatment of glioblastoma (GBM) with alkylating agents is not curative. The protein O6-methylguanine DNA methyltransferase (MGMT) is a significant limitation, being able to repair drug-induced DNA damage. Thus, exploring non-alkylating agents already approved by the FDA is imperative. The antidepressant fluoxetine (FL) has been explored due to its anti-cancer properties. However, its first-pass effect and its non-targeted distribution to brain tissue are major limitations of FL’s administration, which is conventionally orally administered. Thus, the primary objective of this work was the development of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) tailored with folic acid (FA) for FL delivery to GBM cells. Methods: A Central Composite Design (CCD) was applied to optimize the NPs. Results: The developed FA-functionalized PLGA NPs exhibited physicochemical properties suitable for brain-targeted delivery. The final formulation presented an average diameter of 167 ± 8 nm, a polydispersity index (PdI) of 0.23 ± 0.07, and a zeta potential of −22.2 ± 0.3 mV. The encapsulation efficiency (EE) and loading capacity (LC) values were 44.4 ± 3.8% and 3.1 ± 0.3%, respectively. In vitro studies demonstrated that the NPs are stable in storage and simulated physiological conditions and can maintain a controlled and slow-release profile of FL for 17 days. In vitro cell uptake experiments demonstrated that conjugation with FA enhances the NPs’ internalization in GBM cells overexpressing folate receptors through endocytosis mediated by this receptor. Furthermore, in vitro cytotoxicity experiments demonstrated that the FL encapsulation in the developed NPs maintains drug efficacy, as well as it was able to increase cell sensitivity to treatment with an alkylating agent. Conclusions: These results suggest that the developed NPs are effective nanocarriers, either as a standalone therapy or as a chemosensitizer in combination with the standard GBM treatment. Full article

Background: The advances in cancer diagnosis and treatment have significantly improved survival rates in pediatric patients, with five-year survival now exceeding 80% in many high-income countries. However, these life-saving therapies often carry long-term consequences, including impaired fertility. The reproductive health of childhood cancer survivors has emerged as a key issue in survivorship care. Objective: This narrative review aims to examine the gonadotoxic effects of cancer treatments on pediatric patients, evaluate fertility preservation strategies in both males and females, and provide guidance on the long-term monitoring of reproductive function post treatment. Methods: A comprehensive literature review was conducted using PubMed, including randomized trials, cohort studies, and clinical guidelines published up to March 2024. The keywords focused on pediatric oncology, fertility, and reproductive endocrinology. Studies were selected based on relevance to treatment-related gonadotoxicity, fertility preservation options, and follow-up care. Results: Radiotherapy and alkylating agents pose the highest risk to fertility. Postpubertal patients have access to standardized preservation techniques, while prepubertal options remain experimental. Long-term effects include premature ovarian insufficiency, azoospermia, hypogonadism, and uterine dysfunction. The psychosocial impacts, especially in female survivors, are profound and often overlooked. Conclusions: Fertility preservation should be discussed at diagnosis and integrated into treatment planning in pediatric patients with cancer. While options for postpubertal patients are established, more research is needed to validate safe and effective strategies for younger populations. A multidisciplinary approach and long-term surveillance are essential for safeguarding future reproductive potential in childhood cancer survivors. Full article

Chemotherapeutic agents and radiotherapy are highly effective in treating malignancies. However, they carry a significant risk of harming the gonads and may lead to endocrine dysfunction and reproductive issues. This review outlines the molecular mechanisms of gonadotoxic therapies, focusing on radiation, alkylating agents, and platinum compounds. It discusses the loss of PMFs due to gonadotoxic exposure, including DNA double-strand breaks, oxidative stress, and dysregulated signaling pathways like PI3K/PTEN/Akt/mTOR and TAp63-mediated apoptosis. Furthermore, it explores strategies to mitigate gonadal damage, including GnRH agonists, AMH, imatinib, melatonin, sphingolipid metabolites, G-CSF, mTOR inhibitors, AS101, and LH. These therapies, paired with existing fertility preservation methods, could safeguard reproductive and hormonal functions and improve the quality of life for young cancer patients. Despite the progress made in recent years in understanding gonadotoxic mechanisms, gaps remain due to questionable reliance on mouse models and the lack of models replicating human ovarian dynamics. Long-term studies are vital for wider analyses and exploration of protective strategies based on various animal models and clinical trials. It is essential to verify that these substances do not hinder the anti-cancer effectiveness of treatments or cause lasting DNA changes in granulosa cells, raising the risk of miscarriages and infertility. Full article

Methylglyoxal (MGO) is a highly reactive a-dicarbonyl compound produced in foods and endogenously in humans and constitutes a predominant precursor of advanced glycation end products that contribute to the pathology of several diseases, including diabetes and neurodegenerative diseases. In this study, the efficiency of pyrogallol, gallic acid, ethyl, and propyl gallate in trapping MGO was investigated at pH 6.5 to 8.0. Pyrogallol was the most efficient MGO-trapping agent, followed by gallic acid, whereas the alkyl gallates were notably less efficient, particularly at slightly acidic and neutral pH. The increase of pH from slightly acidic to alkaline enhanced the MGO-trapping efficiency of all compounds, albeit to a different extent that correlated inversely to the pK_a of the most acidic -OH phenolic group, demonstrating the contribution of the deprotonated forms of the phenolic compounds in the enhanced reactivity towards MGO. The reaction products of pyrogallol, identified as the most efficient compound in MGO-trapping, were analyzed and characterized by liquid chromatography-mass spectrometry (LC-MS). Both mono-MGO and di-MGO conjugated adducts of pyrogallol were detected, with the mono-MGO adduct being dominant solely at acidic pH and the di-MGO pyrogallol adducts becoming prevalent at neutral and alkaline pH. Therefore, the pH was determined as a main factor that controls the reaction pathways of the phenolic compounds with MGO. Full article

Estradiol (E2) plays an important role in cell proliferation and certain brain functions. To reveal its mechanism of action, its detectability is essential. Only a few fluorescent-labeled hormonally active E2s exist in the literature, and their mechanism of action usually remains unclear. It would be of particular interest to develop novel labeled estradiol derivatives with retained biological activity and improved optical properties. Due to their superior optical characteristics, aza-BODIPY dyes are frequently used labeling agents in biomedical applications. E2 was labeled with the aza-BODIPY dye at its phenolic hydroxy function via an alkyl linker and a triazole coupling moiety. The estrogenic activity of the newly synthesized fluorescent conjugate was evaluated via transcriptional luciferase assay. Docking calculations were performed for the classical and alternative binding sites (CBS and ABS) of human estrogen receptor α. The terminal alkyne function was introduced into the tetraphenyl aza-BODIPY core via selective formylation, oxidation, and subsequent amidation with propargyl amine. The conjugation was achieved via Cu(I)-catalyzed azide–alkyne click reaction of the aza-BODIPY-alkyne with the 3-O-(4-azidobut-1-yl) derivative of E2. The labeled estrogen induced a dose-dependent transcriptional activity of human estrogen receptor α with a submicromolar EC₅₀ value. Docking calculations revealed that the steroid part has a perfect overlap with E2 in ABS. In CBS, however, a head-tail binding deviation was observed. A facile, fluorescent labeling methodology has been elaborated for the development of a novel red-emitting E2 conjugate with substantial estrogenic activity. Docking experiments uncovered the binding mode of the conjugate in both ABS and CBS. Full article

A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound 6k exhibited the highest activity, which was comparable to that of doxorubicin, with IC₅₀ (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development. Full article