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Acta Crystallographica. Section E,... May 2010The title compound, C(20)H(25)N(3)O(2), is a new amonafide analogue, which exhibits anti-tumor activity. The asymmetric unit contains two mol-ecules with similar...
The title compound, C(20)H(25)N(3)O(2), is a new amonafide analogue, which exhibits anti-tumor activity. The asymmetric unit contains two mol-ecules with similar conformations for the substituted aliphatic chains. The two independent mol-ecules form dmers through N-H⋯N hydrogen bonds. The crystal structure is stabilized via π-π stacking inter-actions, the shortest centroid-centroid separation between six-membered rings being 3.673 (2) Å.
PubMed: 21579523
DOI: 10.1107/S1600536810018702 -
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 -
Neoplasia (New York, N.Y.) Jun 2008Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed...
Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide's hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI) using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 microM for 5 successive days) dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Chemokines, CXC; Disease Models, Animal; Humans; Kinetics; Male; Mice; Naphthalimides; Neoplasm Transplantation; Prostatic Neoplasms; Urea
PubMed: 18516294
DOI: 10.1593/neo.08290 -
British Journal of Cancer Jul 2007Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The... (Comparative Study)
Comparative Study
Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER)+/p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER+/p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide.
Topics: Adenine; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Humans; Imides; Isoquinolines; Mice; Mice, Nude; Naphthalimides; Organophosphonates
PubMed: 17551498
DOI: 10.1038/sj.bjc.6603829 -
The Journal of Biological Chemistry May 2001Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage. In the current studies, we show that two different...
Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage. In the current studies, we show that two different classes (ATP-sensitive and -insensitive) of TOP2 poisons can be identified based on their differential sensitivity to the ATP-bound conformation of TOP2. First, in the presence of 1 mm ATP or the nonhydrolyzable analog adenosine 5'-(beta,gamma-imino)triphosphate, TOP2-mediated DNA cleavage induced by ATP-sensitive TOP2 poisons (e.g. doxorubicin, etoposide, mitoxantrone, and 4'-(9-acridinylamino)methanesulfon-m-anisidide) was 30-100-fold stimulated, whereas DNA cleavage induced by ATP-insensitive TOP2 poisons (e.g. amonafide, batracylin, and menadione) was only slightly (less than 3-fold) affected. In addition, ADP was shown to strongly antagonize TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive TOP2 poisons. Second, C427A mutant human TOP2alpha, which exhibits reduced ATPase activity, was shown to exhibit cross-resistance to all ATP-sensitive but not ATP-insensitive TOP2 poisons. Third, using ciprofloxacin competition assay, TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive poisons was shown to be antagonized by ciprofloxacin. These results suggest that ATP-bound TOP2 may be the specific target of ATP-sensitive TOP2 poisons. Using Lac repressor-operator complexes as roadblocks, we show that ATP-bound TOP2 acts as a circular clamp capable of entering DNA ends and sliding on unobstructed duplex DNA.
Topics: Adenosine Triphosphate; Amino Acid Substitution; Amsacrine; Animals; Antineoplastic Agents; Cattle; DNA Topoisomerases, Type II; Doxorubicin; Etoposide; Kinetics; Mitoxantrone; Mutagenesis, Site-Directed; Recombinant Proteins; Teniposide; Thymus Gland
PubMed: 11278845
DOI: 10.1074/jbc.M011143200 -
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 -
British Journal of Cancer Sep 1993Recent studies suggest a high specificity of 99mTc-galactosyl neoglycoalbumin (99mTc-NGA) receptor scanning in vivo by providing both morphological and functional...
Recent studies suggest a high specificity of 99mTc-galactosyl neoglycoalbumin (99mTc-NGA) receptor scanning in vivo by providing both morphological and functional diagnosis of liver disease. In 22 patients with advanced breast cancer 99mTc-NGA (150 MBq; 50 nmol) was exclusively trapped by the liver, the images showing 'cold spots' in areas of liver metastases formation. A two-tailed analysis was performed: the time activity curves recorded for the liver and precordial area were subjected to a kinetic receptor-calculating model allowing an estimation of the NGA-receptor concentration of the liver (i.e. hepatic binding protein, HBP) as well as calculation of the residual functional liver volume (RFLV) via the S.P.E.C.T.-study. In breast cancer patients with liver metastases a significantly (P < 0.01) lower HBP-concentration was estimated (0.65 +/- 0.16 vs 0.82 +/- 0.17 mumol l-1) as evidenced by a lower 99mTc-NGA-accumulation in the liver resulting also in a significantly (P < 0.001) lower RFLV (739 +/- 348 vs 1336 +/- 184 ml). In four amonafide-treated patients (800 mg m-2 intravenous infusion over 3 h) approximately one week after one chemotherapy cycle a significant (P < 0.05) increase in HBP-concentration (0.56 +/- 0.10 vs 0.72 +/- 0.06 mumol l-1) of the liver was found corresponding with an increase in RVLF (546 +/- 297 vs 670 +/- 265 ml). These regulatory mechanisms at the HBP level measured in vivo provide further evidence that 99mTc-NGA should have promise as a clinically useful receptor radiopharmaceutical for both quantification of liver function and assessment of liver morphology.
Topics: Aged; Albumins; Asialoglycoprotein Receptor; Breast Neoplasms; Carrier Proteins; Female; Humans; Isotope Labeling; Liver Neoplasms; Middle Aged; Radionuclide Imaging
PubMed: 8353045
DOI: 10.1038/bjc.1993.384 -
Investigational New Drugs 1993Amonafide (AMF), NSC 308847 is an investigational anticancer drug acting as a DNA intercalating agent. This paper presents results of a phase II clinical study of AMF in... (Clinical Trial)
Clinical Trial
Amonafide (AMF), NSC 308847 is an investigational anticancer drug acting as a DNA intercalating agent. This paper presents results of a phase II clinical study of AMF in disseminated malignant melanoma. Twenty patients, eleven males and nine females, with biopsy proven malignant melanoma, performance status 0-2; median age 59 (range 29-74), and no previous chemotherapy, were treated with AMF 300 mg/m2/day by 60 min i.v. infusion for five days repeated every three weeks. Fifteen patients had lung (9 patients) and/or liver (8 patients) involvement. None had known brain metastasis at entry. All 20 patients were evaluated for response and toxicity. Six patients had stable disease and fourteen had increasing disease. With 0/20 responses, the upper 95% confidence limit for the response rate was 14%. The median survival time was 5.7 months. Hematologic toxicity was dose limiting with the incidence of leucopenia 45% and thrombocytopenia 20%. The nonhematologic toxicities included nausea and vomiting (60%), alopecia (20%), headaches (15%), diarrhea (10%), and phlebitis (10%). We conclude that AMF administered at this dose and schedule is not active in the treatment of patients with malignant melanoma, previously untreated with chemotherapy.
Topics: Adenine; Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Imides; Isoquinolines; Male; Melanoma; Middle Aged; Naphthalimides; Organophosphonates
PubMed: 8262736
DOI: 10.1007/BF00874160