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Bioorganic Chemistry Mar 2024In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives...
In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ctDNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12, the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 (D-12) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV-vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 (D-12) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.
Topics: Humans; HeLa Cells; DNA; Antineoplastic Agents; Carbon; Triazenes; Oxidative Stress; Isoquinolines; Adenine; Organophosphonates
PubMed: 38244381
DOI: 10.1016/j.bioorg.2024.107141 -
The Tohoku Journal of Experimental... Aug 2022The current work screened differentially expressed genes (DEGs) related to advanced clear cell renal cell carcinoma (ccRCC) and found potential biomarkers and drugs for...
The current work screened differentially expressed genes (DEGs) related to advanced clear cell renal cell carcinoma (ccRCC) and found potential biomarkers and drugs for advanced ccRCC. After analyzing GSE53757 and GSE66271, we identified DEGs and performed the functional annotation, pathway enrichment, validation, survival analysis, and candidate drug analysis. We obtained 861 common DEGs from datasets between advanced ccRCC tissues and normal kidney tissues. Besides, we performed functional analysis under ontological conditions and carried out pathway analysis. The five most stable core gene groups and top 10 genes were screened using the Cytoscape software. We performed functional and pathway analyses again and found that the core genes were similar to total DEGs. After verification, the expression trends of the 10 hub genes did not change. Survival analysis showed high expressions of TOP2A, BIRC5, BUB1, MELK, RRM2, and TPX2 genes, suggesting that they might participate in cancer occurrence, migration, and relapse of ccRCC. The gene-drug analysis showed that gallium nitrate, cladribine, and amonafide were strongly associated with RRM2 and TOP2A. We found that RRM2 and TOP2A might be predictive biomarkers and novel targeted therapy for advanced ccRCC. These drugs (gallium nitrate, cladribine, and amonafide) might be used for treating advanced ccRCC.
Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Cladribine; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Neoplasm Recurrence, Local; Prognosis; Protein Serine-Threonine Kinases
PubMed: 35896362
DOI: 10.1620/tjem.2022.J059 -
Chemical Communications (Cambridge,... Apr 2023L-Cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen...
L-Cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (HS) in aqueous and cellular media. Considering the cytoprotective roles of HS, the present adjuvant strategy would be helpful in minimizing the anti-cancer drug-induced side-effects.
Topics: Hydrogen Sulfide; Cysteine; Prodrugs; Antineoplastic Agents; Adjuvants, Immunologic
PubMed: 37000594
DOI: 10.1039/d3cc00220a -
RSC Medicinal Chemistry May 2024A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives 4a-4h with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation...
A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives 4a-4h with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation as antitumor agents. Docking simulation optimization results indicated that biotin-PEG4-piperazine-1,8-naphthalimide 4d should be the best candidate among these designed compounds 4a-4h, and therefore, we synthesized and evaluated it as a novel antitumor agent. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and MGC-803 and U251 xenograft models identified 4d as a good candidate antitumor agent with potent efficacy and safety profiles, compared with amonafide and temozolomide. The findings of the docking simulations, fluorescence intercalator displacement (FID), western blot, comet, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transmission electron microscopy, and BODIPY-581/591-C11, FerroOrange, and dihydroethidium (DHE) fluorescent probe assays revealed that 4d could induce DNA damage, affect DNA synthesis, and cause cell cycle arrest in the S phase in MGC-803 cells. Also, it could induce lipid peroxidation and thus lead to ferroptosis in MGC-803 cells, indicating that it mainly exerted antitumor effects through dual targeting of ferroptosis and DNA. These results suggested that it was feasible to design, optimize using docking simulation, and evaluate the potency and safety of biotin-PEG-1,8-naphthalimide as a antitumor agent with dual targeting of ferroptosis and DNA, based on a multi-target drug strategy.
PubMed: 38784471
DOI: 10.1039/d4md00134f -
European Journal of Medicinal Chemistry Nov 2018In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer... (Review)
Review
In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer agents. The 1,8-naphthalimides binds to the DNA via intercalation, and exert their antitumor activities through Topoisomerase I/II inhibition, photoinduced DNA damage or related mechanism. Here, our discussion focused on works published over the last ten years (2007-2017) related to therapeutic applications, in the order of cancer treatment followed by other properties of 1,8-naphthalimides. In preparing for this review, we considered that several seminal reviews have appeared over the last fifteen years and focused on closely related subjects, however, none of them is exhaustive.
Topics: Antineoplastic Agents; Cell Proliferation; DNA Damage; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA, Neoplasm; Humans; Intercalating Agents; Naphthalimides; Neoplasms; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors
PubMed: 30312931
DOI: 10.1016/j.ejmech.2018.09.055 -
Bioorganic & Medicinal Chemistry Letters Feb 2018A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and...
A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1-NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC values of 2.89, 060, 2.73 and 1.60 μM, respectively, better than the control drug (Amonafide). However, compounds NI5-NI8 conjugated with pyrrole derivatives showed weak cytotoxic activities against the all tested cell lines. Furthermore, their DNA binding properties, fluorescence imaging and cell cycle were investigated. Interestingly, compounds NI1 and NI4 showed fluorescence enhancement because of the strong binding with Ct-DNA, and exhibited fluorescence imaging with Hela cells on the lysosomes.
Topics: Adenine; Animals; Antineoplastic Agents; Cell Line, Tumor; DNA; Drug Screening Assays, Antitumor; Fluorescence; Fluorescent Dyes; Humans; Lysosomes; Microscopy, Confocal; Microscopy, Fluorescence; Naphthalimides; Nucleic Acid Conformation; Organophosphonates; Piperazines; Piperidines; S Phase Cell Cycle Checkpoints; Transition Temperature; Zebrafish
PubMed: 29342415
DOI: 10.1016/j.bmcl.2018.01.008 -
Food Safety (Tokyo, Japan) Dec 2022Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human...
Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human CYP-Template systems developed in our previous studies (Drug Metab Pharmacokinet 2019, 2021, 2022). Simulation experiments of a topoisomerase-targeting agent, amonafide, offered a possible new inhibitory-mechanism as Trigger-residue inactivation on human CYP1A2 Template. -Acetylamonafide as well as amonafide would inactivate CYP1A2 through the interference of Trigger-residue movement with their dimethylaminoethyl parts. The mechanism was also supported on the inhibition/inactivation of two other drugs, DSP-1053 and binimetinib. Both the drugs, after other CYP-mediated slight structural alterations, were expected to interact with Trigger-residue for the intense inhibition on CYP1A2 Template. Possible formation of reactive intermediates of amonafide and 3-methylindole was also examined on CYP1A2 Template. Placements of amonafide suggested the scare -oxidation of the arylamine part due to the Trigger-residue interaction. Placements of 3-methylindole suggested the formation of a reactive intermediate, 3-methyleneindolenine, rather selectively on rodent CYP1A2 than on human CYP1A2, in consistent with the experimental data. These results suggest that CYP Template systems developed are effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.
PubMed: 36619007
DOI: 10.14252/foodsafetyfscj.D-22-00008 -
European Journal of Medicinal Chemistry Oct 2021Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic...
Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic drugs and the ineffectiveness of current therapies. Recently polyamine derivatives have been identified as a promising prospect in dealing with metastatic tumors. Herein, a novel class of naphthalimide-polyamine conjugates 8a-8d, 13a-13c, 17 and 21 were synthesized and the mechanism was further determined. The polyamine conjugate 13b displayed remarkably elevated anti-tumor and anti-metastatic effects (76.01% and 75.02%) than the positive control amonafide (46.91% and 55.77%) at 5 mg/kg in vivo. The underlying molecular mechanism indicated that in addition to induce DNA damage by up-regulating p53 and γH2AX, 13b also targeted lysosome to modulate polyamine metabolism and function in a totally different way from that of amonafide. Furthermore, the HMGB1/p62/LC3II/LC3I and p53/SSAT/β-catenin pathways were mainly involved in the inhibition of 13b-induced HCC metastasis by targeting polyamine transporters (PTs) overexpressed in HCC. At last, 13b down-regulated the concentrations of Put, Spd and Spm by modulating polyamine metabolism key enzymes SSAT and PAO, which favored the suppression of fast growing tumor cells. Taken together, our study implies a promising strategy for naphthalimide conjugates to treat terminal cancer of HCC by targeting autophagy and tumor microenvironment with reduced toxicities and notable activities.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Lysosomes; Molecular Structure; Naphthalimides; Polyamines; Structure-Activity Relationship
PubMed: 33965862
DOI: 10.1016/j.ejmech.2021.113469 -
Cancers Nov 2023: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver...
: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver cancer, necessitating an in-depth understanding of the underlying molecular alterations for improved treatment. : We searched for a vast array of microarray experiments in addition to RNA-seq data. Through rigorous filtering processes, we have identified highly representative differentially expressed genes (DEGs) between tumor and non-tumor liver tissues and identified a distinct class of possible new candidate drugs. : Functional enrichment analysis revealed distinct biological processes associated with metal ions, including zinc, cadmium, and copper, potentially implicating chronic metal ion exposure in tumorigenesis. Conversely, up-regulated genes are associated with mitotic events and kinase activities, aligning with the relevance of kinases in HCC. To unravel the regulatory networks governing these DEGs, we employed topological analysis methods, identifying 25 hub genes and their regulatory transcription factors. In the pursuit of potential therapeutic options, we explored drug repurposing strategies based on computational approaches, analyzing their potential to reverse the expression patterns of key genes, including AURKA, CCNB1, CDK1, RRM2, and TOP2A. Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. : This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.
PubMed: 38067357
DOI: 10.3390/cancers15235653 -
The Analyst Jun 2021Glioblastoma is the most common and aggressive type of malignant brain tumor with poor survival and limited therapeutic options. Theranostic anticancer agents with dual...
Glioblastoma is the most common and aggressive type of malignant brain tumor with poor survival and limited therapeutic options. Theranostic anticancer agents with dual functions of diagnosis and therapy are highly attractive. Self-immolation reaction is a promising approach for theranostic prodrugs triggered by the tumor microenvironment. Overexpression of hydrogen sulfide (HS) in glioma cells becomes a potential stimulus for activating prodrugs. Herein, a novel HS responsive agent (SNF) containing amonafide (ANF), a self-immolative linker and a trigger group has been developed for imaging and chemotherapy in living cells. SNF exhibited high selectivity and sensitivity towards HS and also showed excellent lysosome-targeted capability. The activated SNF could translocate to the nucleus, causing DNA damage and blocking the cell cycle. More mechanistic studies indicated that SNF altered the mitochondrial membrane potential and induced autophagy in human glioblastoma-astrocytoma (U87MG). In addition, 3D multicellular U87MG tumor spheroids were used to further confirm the active drug release and high anti-proliferative activity of SNF. This approach may provide a general strategy for developing HS-triggered prodrugs for synergic cancer therapy.
Topics: Brain Neoplasms; Cell Line, Tumor; Drug Liberation; Glioblastoma; Humans; Hydrogen Sulfide; Lysosomes; Tumor Microenvironment
PubMed: 33908968
DOI: 10.1039/d1an00457c