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MedChemComm Jan 2019A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their cytotoxicity on selected human cancer cell...
A new series of different naphthalimide-benzothiazole/cinnamide derivatives were designed, synthesized and tested for their cytotoxicity on selected human cancer cell lines. Among them, derivatives and with the 6-aminobenzothiazole ring and with the cinnamide ring displayed potent cytotoxic activity against colon (IC: 3.715 and 3.467 μM) and lung cancer (IC: 4.074 and 3.890 μM) cell lines when compared to amonafide (IC: 5.459 and 7.762 μM). Later, the DNA binding studies for these selected derivatives (by CD, UV/vis, fluorescence spectroscopy, DNA viscosity, and molecular docking) suggested that these new derivatives significantly intercalate between two strands of DNA. In addition, the most potent derivatives and were also found to inhibit DNA topoisomerase-II.
PubMed: 30774856
DOI: 10.1039/c8md00395e -
Nucleic Acids Research Jan 1995A number of antitumor drugs including naphthalimides, a new class of intercalating agents, interfere with the DNA breakage-reunion activity of mammalian DNA...
A number of antitumor drugs including naphthalimides, a new class of intercalating agents, interfere with the DNA breakage-reunion activity of mammalian DNA topoisomerase II resulting in DNA cleavage stimulation. In this work, the sequence specificity of a lead compound of this series, amonafide, in stimulating DNA cleavage by murine topoisomerase II has been studied. Amonafide-stimulated cleavage intensity patterns were markedly different from those of other antitumor drugs by using pBR322 and SV40 DNAs. This drug had an unusually high site selectivity since about 60% of DNA cleavage was observed at only one site in pBR322 DNA, and at two sites in SV40 DNA. A total of ninety-four drug-stimulated sites were collected, and a statistical analysis of their sequences showed that amonafide highly prefers a cytosine, and excludes guanines and thymines instead, at position -1. A lower preference for an adenine at position +1 was also noted. In agreement with the statistical analysis, the DNA sequences of the three sites stimulated by amonafide at exceptionally high levels showed that the drug requirements of a cytosine (-1) and adenine (+1) were present in both the two strands. In addition, a particular feature of these prominent cleavage sites was the presence of an inverted repeat from position -3 to +7. Comparison of amonafide stimulation of DNA cleavage in oligonucleotides bearing base mutations at positions -2, -3 and/or +6, +7 suggested that DNA sequence, and not a putative cruciform structure, was critical for drug action. Moreover, the results showed that, for strong cleavage stimulation, the primary drug requirements at -1 and +1 positions were not sufficient and that the sequence 5'-WRC decreases A-3' (W, A or T; R, A or G) is required from -3 to +1 positions at both strands. The results suggest that the exceptionally high sequence specificity of amonafide is the result of optimal drug interactions with both the two enzyme subunits.
Topics: Adenine; Animals; Antineoplastic Agents; Base Sequence; Binding Sites; DNA; DNA Topoisomerases, Type II; DNA, Viral; Imides; Isoquinolines; Leukemia P388; Mice; Molecular Sequence Data; Naphthalimides; Organophosphonates; Sequence Analysis, DNA; Simian virus 40
PubMed: 7862525
DOI: 10.1093/nar/23.2.223 -
Molecules (Basel, Switzerland) Oct 2016A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide...
A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC (50% effective concentration) = 27.6-91.5 μM]. Compound exhibited the highest activity against a thymidine kinase-deficient (TK) VZV strain (EC = 27.59 μM), while was the most potent towards TK⁺ VZV (EC = 29.91 μM). Cytostatic properties of the compounds --- were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC (50% inhibitory concentration) = 29-130 µM] and L1210 cells [IC (50% inhibitory concentration) = 14-142 µM].
Topics: Adenine; Antiviral Agents; Cell Line; Cell Proliferation; Cytostatic Agents; HeLa Cells; Herpesvirus 3, Human; Humans; Inhibitory Concentration 50; Molecular Structure; Naphthalimides; Organophosphonates
PubMed: 27792200
DOI: 10.3390/molecules21111420 -
Theranostics 2015Magnetic resonance imaging (MRI)-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy. These alginate microspheres...
Magnetic resonance imaging (MRI)-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy. These alginate microspheres were synthesized using a highly efficient microfluidic gelation process. The microspheres included magnetic clusters formed by USPIO nanoparticles to permit MRI and a sustained drug-release profile. The biocompatibility, MR imaging properties and amonafide release kinetics of these microspheres were investigated during in vitro studies. A xenograft rodent model was used to demonstrate the feasibility to deliver these microspheres to liver tumors using hepatic transcatheter intra-arterial infusions and potential to visualize the intra-hepatic delivery of these microspheres to both liver tumor and normal tissues with MRI immediately after infusion. This approach offer the potential for catheter-directed drug delivery to liver tumors for reduced systemic toxicity and superior therapeutic outcomes.
Topics: Adenine; Alginates; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Carriers; Glucuronic Acid; Hexuronic Acids; Injections, Intra-Arterial; Liver Neoplasms; Magnetic Resonance Imaging; Microspheres; Naphthalimides; Organophosphonates; Rats
PubMed: 25767615
DOI: 10.7150/thno.10823 -
Antimicrobial Agents and Chemotherapy 2014Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the...
Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.
Topics: Antifungal Agents; Antineoplastic Agents; Candida; Clinical Trials as Topic; Drug Discovery; Drug Repositioning; Drug Resistance, Fungal; Glycine; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Microbial Sensitivity Tests; Small Molecule Libraries
PubMed: 24277040
DOI: 10.1128/AAC.01087-13 -
Acta Biomaterialia Feb 2014Recently, 6-methoxyethylamino numonafide (MEAN) exhibited potent inhibition of hepatocellular carcinoma (HCC) cell growth and less systemic toxicity than amonafide. MEAN...
Recently, 6-methoxyethylamino numonafide (MEAN) exhibited potent inhibition of hepatocellular carcinoma (HCC) cell growth and less systemic toxicity than amonafide. MEAN may serve as an ideal candidate for the treatment of HCC; however, liver-directed, selective infusion methods may be critical to maximize the MEAN dose delivered to the targeted tumors. This study describes the microfluidic fabrication of MEAN-eluting ultrasmall superparamagnetic iron oxide (USPIO) nanocluster-containing alginate microspheres (MEAN-magnetic microspheres) intended for selective transcatheter delivery to HCC. The resulting drug delivery platform was mono-disperse, microsphere sizes were readily controlled based on channel flow rates during synthesis procedures, and drug release rates from the microspheres could be readily controlled with the introduction of USPIO nanoclusters. The MR relaxivity properties of the microspheres suggest the feasibility of in vivo imaging after administration, and these microspheres exhibited potent therapeutic effects significantly inhibiting cell growth inducing apoptosis in hepatoma cells.
Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Dextrans; Humans; Liver Neoplasms; Magnetic Phenomena; Magnetic Resonance Spectroscopy; Magnetite Nanoparticles; Microfluidics; Microspheres; Naphthalimides; Particle Size
PubMed: 24161384
DOI: 10.1016/j.actbio.2013.10.018 -
Cellular and Molecular Bioengineering Oct 2017Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer with high resistance to current standard therapies. We demonstrate that phenotypically...
INTRODUCTION
Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer with high resistance to current standard therapies. We demonstrate that phenotypically stratified carbon nanoparticle is highly effective in delivering a novel combinatorial triple drug formulation for synergistic regression of TNBC and .
METHOD
The combinatorial formulation is comprised of repurposed inhibitors of STAT3 (nifuroxazide), topoisomerase-II-activation-pathway (amonafide) and NFκb (pentoxifylline). Synergistic effect of drug combination was established in a panel of TNBC-lines comprising mesenchymal-stem-like, mesenchymal and basal-like cells along with non-TNBC-cells. The delivery of combinatorial drug formulation was achieved using a phenotypically screened carbon nanoparticles for TNBC cell lines.
RESULTS
Results indicated a remarkable five-fold improvement (IC50-6.75 M) from the parent drugs with a combinatorial index <1 in majority of the TNBC cells. Multi-compartmental carbon nanoparticles were then parametrically assessed based on size, charge (positive/negative/neutral) and chemistry (functionalities) to study their likelihood of crossing endocytic barriers from phenotypical standpoint in TNBC lines. Interestingly, a combination of clathrin mediated, energy and dynamin dependent pathways were predominant for sulfonated nanoparticles, whereas pristine and phospholipid particles followed all the investigated endocytic pathways.
CONCLUSIONS
An exactitude 'omics' approach helps to predict that phospholipid encapsulated-particles will predominantly accumulate in TNBC comprising the drug-'cocktail'. We investigated the protein expression effects inducing synergistic effect and simultaneously suppressing drug resistance through distinct mechanisms of action.
PubMed: 31719869
DOI: 10.1007/s12195-017-0490-y -
Neoplasia (New York, N.Y.) Nov 2009Naphthalimides, particularly amonafide and 2-(2-dimethylamino)-6-thia-2-aza-benzo[def]chrysene-1,3-diones (R16), have been identified to possess anticancer activities...
Naphthalimides, particularly amonafide and 2-(2-dimethylamino)-6-thia-2-aza-benzo[def]chrysene-1,3-diones (R16), have been identified to possess anticancer activities and to induce G(2)-M arrest through inhibiting topoisomerase II accompanied by Chk1 degradation. The current study was designed to precisely dissect the signaling pathway(s) responsible for the naphthalimide-induced cell cycle arrest in human colon carcinoma HCT116 cells. Using phosphorylated histone H3 and mitotic protein monoclonal 2 as mitosis markers, we first specified the G(2) arrest elicited by the R16 and amonafide. Then, R16 and amonafide were revealed to induce phosphorylation of the DNA damage sensor ataxia telangiectasia-mutated (ATM) responding to DNA double-strand breaks (DSBs). Inhibition of ATM by both the pharmacological inhibitor caffeine and the specific small interference RNA (siRNA) rescued the G(2) arrest elicited by R16, indicating its ATM-dependent characteristic. Furthermore, depletion of Chk2, but not Chk1 with their corresponding siRNA, statistically significantly reversed the R16- and amonafide-triggered G(2) arrest. Moreover, the naphthalimides phosphorylated Chk2 in an ATM-dependent manner but induced Chk1 degradation. These data indicate that R16 and amonafide preferentially used Chk2 as evidenced by the differential ATM-executed phosphorylation of Chk1 and Chk2. Thus, a clear signaling pathway can be established, in which ATM relays the DNA DSBs signaling triggered by the naphthalimides to the checkpoint kinases, predominantly to Chk2,which finally elicits G(2) arrest. The mechanistic elucidation not only favors the development of the naphthalimides as anticancer agents but also provides an alternative strategy of Chk2 inhibition to potentiate the anticancer activities of these agents.
Topics: Adenine; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; Cell Cycle Proteins; Checkpoint Kinase 2; DNA Breaks, Double-Stranded; DNA-Binding Proteins; Flow Cytometry; Fluorescent Antibody Technique; G2 Phase; HCT116 Cells; Humans; Naphthalimides; Organophosphonates; Protein Serine-Threonine Kinases; RNA, Small Interfering; Signal Transduction; Thiophenes; Transfection; Tumor Suppressor Proteins
PubMed: 19881958
DOI: 10.1593/neo.09986 -
Molecules (Basel, Switzerland) Jun 2014A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five...
A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five cancer cell lines (HCT-116, PC-3, U87 MG, Hep G2 and SK-OV-3). Several compounds displayed better activities than the control compound amonafide. Further evaluations by fluorescence spectroscopy studies and DNA-interstrand cross-linking assays revealed that the derivatives showed both alkylating and intercalating properties. Among the derivatives, the bis-naphthalimide N-mustard derivative 11b was found to exhibit the highest cytotoxic activity and DNA cross-linking ability. Both 11b and 7b induce HCT-116 cell apoptosis by S phase arrest.
Topics: Antineoplastic Agents, Alkylating; Apoptosis; Cell Cycle Checkpoints; Drug Screening Assays, Antitumor; HCT116 Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Naphthalimides; Phosphoramide Mustards; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases
PubMed: 24968335
DOI: 10.3390/molecules19078803 -
Molecules (Basel, Switzerland) Nov 2016Three types of conjugates in which aromatic imide scaffolds were coupled to diverse amine/polyamine motifs were synthesized, and their antitumor activities were...
Three types of conjugates in which aromatic imide scaffolds were coupled to diverse amine/polyamine motifs were synthesized, and their antitumor activities were evaluated in vitro and in vivo. Results showed that the conjugate of 1,8-naphthilimide with spermine had pronounced effects on inhibiting tumor cell proliferation and inducing tumor cell apoptosis via ROS-mediated mitochondrial pathway. The in vivo assays on three H22 tumor transplant models revealed that compound exerted potent ability in preventing lung cancer metastasis and extending lifespan. Furthermore, the efficacy of in inhibiting tumor growth and improving body weight index were better than that of positive control, amonafide. Our study demonstrates that compound is a valuable lead compound for further investigation.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Imides; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mice; Polyamines; Xenograft Model Antitumor Assays
PubMed: 27916902
DOI: 10.3390/molecules21121637