Search Results (462)

Alkyladenine DNA glycosylase (AAG) is a critical enzyme in the base excision repair (BER) pathway, responsible for removing a broad spectrum of alkylated DNA lesions. While AAG maintains genomic stability, dysregulated activity has been implicated in cancer development, drug resistance, and neurodegenerative diseases. This review synthesizes the current knowledge on AAG’s structure, catalytic mechanism, and polymorphic variants, highlighting their potential roles in disease pathogenesis. A comprehensive bioinformatics analysis of over 370 AAG single-nucleotide polymorphisms (SNPs) is presented, identifying ~40% as high-risk variants likely to impair enzymatic function. Notably, 151 SNPs were predicted to be damaging by multiple algorithms, including substitutions at catalytic residues and non-conserved sites with unknown functional consequences. Analysis of cancer databases (COSMIC, cBioPortal, NCBI) revealed 93 tumor-associated AAG variants, with 18 classified as high-impact mutations. This work underscores the need for mechanistic studies of AAG variants using structural biology, cellular models, and clinical correlation analyses. Deciphering AAG’s polymorphic landscape may unlock personalized strategies for cancer prevention and treatment. 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

This study focuses on the search for new effective synthetic antimicrobial compounds as a tool against the widespread presence of microorganisms resistant to existing drugs. Five derivatives of [1,3]thiazolo[3,2-b][1,2,4]triazoles were synthesized using an accessible protocol based on electrophilic heterocyclization and were characterized using infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies, and their in vitro antimicrobial and antifungal activities were evaluated using the agar plate diffusion method and the microdilution plate procedure. Both antibacterial (Gram-positive and Gram-negative) and antifungal activities were found for the examined samples. The minimum inhibitory concentration (MIC) varied from 0.97 to 250 µg/mL, and the minimum bactericidal concentration (MBC) from 1.95 to 500 µg/mL. Compound 2a showed good antifungal action against Candida albicans and Saccharomyces cerevisiae with minimum fungicidal concentration (MFC) 125 and MIC 31.25 µg/mL. The molecular docking revealed that the 2-heptyl-3-phenyl-6,6-trimethyl-5,6-dihydro-3H-[1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium cation stands out as a highly promising candidate for further investigation due to a wide range of interactions, including conventional hydrogen bonds, π–σ, π–π T-shaped, and hydrophobic alkyl interactions. The synthesis and preliminary evaluation of [1,3]thiazolo[3,2-b][1,2,4]triazoles yielded promising antimicrobial and antifungal candidates. The diverse interaction profile of the 2-heptyl derivative salt allows this compound’s selection for further biological studies. Full article

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guanidinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of Transmembrane Serine Protease 2 (TMPRSS2), a human protease that is essential for infection by many respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Our in vitro fluorescence-based protease assays and supporting computational docking studies suggest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC₅₀ = 1–3 nM, BE = −6.6 to −7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerge as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaffolds for the future development of targeted antiviral therapeutics. Replacement of camostat’s ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug’s known role as an acylating suicide inhibitor. Docking studies confirm that the replacement of aromatic residues with flexible, equivalent-length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further analogues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure–activity relationship studies. Further investigation will support tailoring this class of drugs for repurposing in antiviral therapy. Full article

The emergence of antifungal-resistant Aspergillus fumigatus (A. fumigatus) became a serious public health concern, underscoring the need for new effective antifungal agents. Here, we present a strategy based on the in situ generation of radical species that are toxic to the pathogen. The synthesis of an alkoxyamine linked to a peptide substrate recognized by A. fumigatus-secreted dipeptidyl peptidase is described. Kinetic experiments show a stable prodrug prior to enzymatic activation. Ensuing peptide cleavage and spontaneous homolysis resulted in the generation of a stable nitroxide and a reactive alkyl radical moiety. Next, the exposure of A. fumigatus spores to the prodrug lead to pathogen growth inhibition in a compound concentration-dependent fashion (e.g., 42% inhibition at 10 µg/L). Importantly, the designed alkoxyamine inhibited not only the growth of a clinical voriconazole-susceptible A. fumigatus strain, but also the growth of a strain resistant to this azole. To determine the antifungal importance of the reactive alkyl radical, its substitution with a non-radical structure did not prevent A. fumigatus growth. Furthermore, the introduction of succinic group in the peptide substrate resulted in the loss of alkoxyamine antifungal properties. Our work reports a novel chemical strategy for antifungal therapy against A. fumigatus based on the pathogen enzyme-mediated generation of toxic radicals. Significantly, these findings are timely since they could overcome the emerged resistance to conventional drugs that are known to target defined pathogen biologic mechanisms such as ergosterol synthesis. Full article

Background: Ifosfamide, an alkylating agent used for treating various cancers, can cause encephalopathy in 10–30% of adults and 8% of children. Methylene blue has been used to treat ifosfamide-induced encephalopathy (IIE). This study aimed to describe our institutional experience with IIE in children and young adults with cancer, including its clinical manifestations, treatment, and outcomes. Methods: We reviewed the clinical records of patients with cancer aged up to 30 years who developed IIE over 10 years. Results: Twenty-four patients (median age: 17.6 years, range: 4–30 years) were included; 54% were male, and 71% had bone/soft tissue sarcomas. Ifosfamide was administered alone or with other drugs (dose range: 1.5–3.3 g/m²/day). Twelve patients developed IIE after short intermittent infusions (1–3 h), and twelve developed it after continuous infusions (12–24 h). IIE occurred at a median cumulative ifosfamide dose of 18 g/m². Symptoms appeared within hours to five days and resolved within 24–120 h. An altered mental status was present in all except one patient. Twelve patients had grade 3 IIE (severe somnolence, agitation, and confusion), and five had grade 4 IIE (coma and seizures). Twenty patients (83%) received methylene blue, with symptom resolution in nineteen patients (83%). Imaging studies showed nonspecific findings. Ten patients were re-challenged with ifosfamide; five received prophylactic methylene blue treatment, of whom three had recurrence. Conclusions: IIE can occur with both short intermittent and continuous ifosfamide infusions and presents as an altered mental status, seizures, and, rarely, hemiparesis. Symptoms are transient, and methylene blue may help alleviate this neurotoxicity, but it does not completely prevent its recurrence. Full article

Fanconi anemia (FA) is characterized by faulty DNA repair and is associated with bone marrow failure, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Because of the more widespread use of next-generation sequencing (NGS) and increased testing for germline mutations in young patients with MDS and AML, FA is increasingly being first diagnosed in adults, many of whom lack classical physical stigmata. Hematopoietic stem cell transplant is the only cure for the hematologic manifestations of FA but there are several unique considerations in FA patients, including first maintaining a high index of suspicion for the diagnosis in patients with minimal phenotypic abnormalities, second an exaggerated sensitivity to alkylating agents and radiation, precluding the use of standard myeloablative conditioning regimens despite the young age of most of the patients, and lastly a marked propensity for squamous cell cancers of the upper aerodigestive tract and anogenital region, likely further increased by the drugs used in conditioning and by chronic inflammation in patients who develop graft-versus-host disease. Despite a growing number of FA patients surviving into adulthood or first being diagnosed with FA as an adult, there is minimal literature describing transplant methodology and outcomes. In the following case-based review of a patient, we incorporate recent findings from the literature on the care of this challenging patient population. Full article

Heteroaromatic motifs are prevalent in natural products and numerous high-value drug molecules. Consequently, the construction of alkylated heterocyclic frameworks holds significant importance. The Minisci reaction of heteroarenes has evolved into a flexible technique for the synthesis of substituted heterocyclic derivatives. However, the use of strong oxidants and external acid is inevitable during the reaction process. Herein, we present a versatile and accessible method for achieving cross dehydrogenation coupling between quinoline derivatives and inactive ether. This strategy utilizes inexpensive NaI and PPh₃ to support the reaction, obviating the need for metal complexes or sacrificial oxidants, and enables the straightforward synthesis of a diverse library of alkyl-substituted N-heteroarenes. Additionally, radical trapping experiments and fluorescence quenching experiments have been conducted to gain a more comprehensive understanding of the reaction mechanism. Full article

The synthesis of a series of six chloro[N-alkyl-N-cinnamyl-benzimidazol-2-yliden]silver(I) complexes was successfully achieved, wherein allyl (3a), methoxymethyl (3b), benzyl (3c), 3-fluorobenzyl (3d), 4-fluorobenzyl (3e) and 4-methyl-benzyl (3f) substituents were grafted on the benzimidazole ring. The isolated silver N-heterocyclic carbene (NHC) complexes were identified by microanalyses and mass spectrometry and characterized by FT-IR and NMR spectroscopic techniques. Conclusive evidence for the structures of complexes 3c and 3d was provided by single-crystal X-ray crystallography. The in vitro inhibitory activity of the six Ag-NHC complexes was tested against trophozoites and cysts of the pathogenic Acanthamoeba castellanii strain and the efficacy sequence is as follows: 3d > 3c > 3f > 3a > 3b > 3e. At a concentration of 100 µM in complexes 3c, 3d and 3f and after 72 h of incubation, 5.3, 3.2 and 6.3% A. castellanii trophozoite viabilities were observed, respectively. The utilization of elevated silver(I) drug concentrations, 1000 µM, resulted in the near-total eradication of pathogenic protozoa. Full article

Platinum resistance represents an urgent medical need in the management of ovarian cancer. The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). Two PDX models were selected from our xenobank: one with acquired resistance to DDP (#266R) and the other (#315) with intrinsic DDP resistance. Tumor-bearing mice were randomized to receive vehicle, single onvansertib, gemcitabine and carboplatin, and their combinations. Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated. In the #266R model, single drug treatments were completely inactive, while the combinations of onvansertib/gemcitabine and onvansertib/carboplatin resulted in a significant increase in survival compared to controls and single drugs (p < 0.001 versus control, onvansertib, gemcitabine and carboplatin). Similar efficacy was observed in the s.c. #315 PDX model; indeed, onvansertib and carboplatin monotherapies were inactive, gemcitabine monotherapy was marginally active, while both combinations were highly active. The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability. Full article

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Alkylating agents, historically employed as chemical warfare agents and currently used as chemotherapeutic drugs, are known to induce significant pulmonary toxicity. Current clinical interventions often fail to fully prevent or reverse these pathological changes, highlighting the urgent need for safe, broad-spectrum therapeutic agents that are effective across diverse exposure scenarios. Melatonin has emerged as a promising protective agent due to its antioxidant, anti-inflammatory, and immunomodulatory properties, along with a well-established safety profile. This systematic review evaluates the potential of melatonin in mitigating vesicant-induced pulmonary damage, synthesizing and critically analyzing preclinical evidence in accordance with the PRISMA guidelines. Three in vivo rodent studies met the inclusion criteria and were analyzed. In all cases, melatonin demonstrated protective effects against alkylating agents such as mechlorethamine (HN2) and cyclophosphamide (CP). These effects were dose-dependent and observed across various animal models, administration protocols, and dosages (ranging from 2.5 to 100 mg/kg), highlighting the importance of context-specific considerations. The human equivalent doses (HEDs) ranged from 12 to 973 mg per day, suggesting that the effective doses may exceed those typically used in clinical trials for other conditions. Melatonin’s pleiotropic mechanisms, including a reduction in oxidative stress, the modulation of inflammatory pathways, and support for tissue repair, reinforce its therapeutic potential in both prophylactic and treatment settings for alkylating agent exposure. Nonetheless, this review underscores the critical need for further randomized clinical trials to establish the optimal dosing strategies, refine treatment protocols, and fully elucidate melatonin’s role in managing alkylating-agent-induced pulmonary toxicity. Full article

Cyanohydrin synthesis, as the simplest preparative method for introducing a carboxyl group into a piperidine molecule, has been used to obtain potentially biologically active piperidinecarboxylic acids, which have alkyl and arylalkyl radicals at the nitrogen atom of the piperidine ring. Hydrochlorides of cyclopropanecarboxylic acid esters based on piperidinecarboxylic acids, as well as hydrochlorides of fluorobenzoic acid esters of N-substituted piperidines, have been synthesized. The purpose of this study was to search for antiviral drugs among new piperidine derivatives. The structure of the synthesized compounds was studied by NMR methods, including COSY (¹H-¹H), HMQC (¹H-¹³C) and HMBC (¹H-¹³C) techniques. The values of chemical shifts, multiplicities, and integrated intensities of ¹H and ¹³C signals in one-dimensional NMR spectra were determined. The results of COSY (¹H-¹H), HMQC (¹H-¹³C), and HMBC (¹H-¹³C) revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral and cytotoxic activities of the synthesized compounds were studied. The antiviral activity in vitro was determined according to the therapeutic regimen against the influenza A/Swine/Iowa/30 (H1N1) virus on the MDCK cell model. The cytotoxicity of the studied substances in vitro was assessed using the MTT test. Based on the results of the antiviral activity against the influenza A virus, it can be concluded that all substances are effective against the influenza A/H1N1 virus compared to the commercial preparations Tamiflu and Rimantadine. Full article

Benzimidazole derivatives are well known for their anthelmintic activity. Investigating the potential efficacy of new derivatives of this class against various parasites is essential to identify novel drug candidates. For this purpose, an in-house molecular database was screened, and four benzimidazole-based molecules were chosen to evaluate antiprotozoal activity. The compounds (K1–K4) had been previously synthesized through a four-step procedure. The potential in vitro cytotoxic properties of the compounds were assessed against the Leishmania (L.) major strain and L929 mouse fibroblast cells. The tests indicated that K1 (3-Cl phenyl) demonstrated an antileishmanial effect (IC₅₀ = 0.6787 µg/mL) and cytotoxicity at elevated concentrations (CC₅₀ = 250 µg/mL) in healthy cells. These findings were comparable to those of AmpB. The antileishmanial activity values were determined as follows: K2; 8.89 µg/mL, K3; 45.11 µg/mL, K4; and 69.19 µg/mL. The CC₅₀ values were determined as follows: K2, 63 µg/mL; K3; 0.56 µg/mL; and K4, 292 µg/mL. Molecular docking and dynamic simulations were conducted to elucidate the potential mechanisms of action of the test substances. In silico investigations indicated interactions between the compounds and the active site of pteridine reductase 1 (PTR1), which is a biosynthetic enzyme essential for parasite proliferation. N-alkyl benzimidazole-based compounds exhibit potential inhibitory activity against L. (L.) major promastigotes. Therefore, these findings suggest that in vivo evaluation is warranted, and structural modifications may lead to the identification of more effective antileishmanial agents. Full article

Metabolic enzymes and cancer-driving transcriptions factors are often overexpressed in neoplastic cells, and their exposed cysteine residues are amenable to chemical modification. This review explores cysteine alkylation as a cancer treatment strategy, focusing on Michael acceptors like curcumin and helenalin, which interact with transcription factors NF-κB, STAT3 and HIF-1α. Molecular docking studies using AutoDockFR revealed distinct binding affinities: curcumin showed strong interactions with STAT3 and NF-κB, while helenalin exhibited high affinity for STAT3 and HIF-1α. Synthetic compounds like STAT3-IN-1 and CDDO-Me demonstrated superior binding in most targets, except for CDDO-Me with HIF-1α, suggesting unique structural incompatibilities. Natural products such as zerumbone and umbelliferone displayed moderate activity, while palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand−receptor structural complementarity, particularly for HIF-1α’s confined binding site, where helenalin’s terminal Michael acceptor system proved optimal. The findings advocate for integrating computational and experimental approaches to develop cysteine-targeted therapies, balancing synthetic precision with natural product versatility for context-dependent cancer treatment strategies. Full article