2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent

Sami, Salah M.; Dorr, Robert T.; Alberts, David S.; Remers, William A.

doi:10.1021/jm00058a014

Cited by 57 publications

(87 citation statements)

References 13 publications

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“…However, amonafide is extensively metabolised, including N-acetylation to an active metabolite, N-acetyl amonafide, and the extent of amonafide N-acetylation is the major determinant of myelosuppression . As a result, several compounds having structural analogy to amonafide have been synthesized (Sami et al, 1993(Sami et al, , 2000Dorr et al, 2001). Among these, azonafide has shown high potency against a panel of human colon cancer cell lines and was active against i.p.…”

Section: Discussionmentioning

confidence: 99%

“…Among these, azonafide has shown high potency against a panel of human colon cancer cell lines and was active against i.p. P388 leukaemia and s.c. B16 melanoma murine models (Sami et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Naphthalimides were designed by combining structural components of several antitumour compounds into a small molecule and have shown high antitumour activity upon a variety of murine and human tumour cells (Brana and Ramos, 2001). One of these compounds, amonafide (Sami et al, 1993) has been verified to exert ATPindependent topo II-mediated DNA cleavage (Andersson et al, 1987;Hsiang et al, 1989;Dorr et al, 2001). Furthermore, this agent is not affected by the multidrug resistance phenomenon and is not an efflux pump substrate (Dorr et al, 2001).…”

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confidence: 99%

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Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Alami

Paterson²,

Bélanger

et al. 2007

Br J Cancer

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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) þ /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 þ /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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Alami

Paterson²,

Bélanger

et al. 2007

Br J Cancer

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“…Several topo II inhibitors are currently under clinical studies against solid tumors. [12][13][14] Amonafide (3), 15) which is the basis of our drug design in this program, is also a topo II inhibitor on which intensive clinical studies were conducted in the mid 1990s. In 2003, a phase study was launched in the United States to evaluate amonafide as a potential therapeutic for solid tumors.…”

Section: )mentioning

confidence: 99%

Synthesis and Evaluation of Novel Pyrimido-Acridone, -Phenoxadine, and -Carbazole as Topoisomerase II Inhibitors

Kamata

Okada

Kotake

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Topoisomerase II (Topo II)-inhibiting antineoplastic agents, such as etoposide and doxorubicin are among the most effective antitumor drugs currently available for the treatment of human cancers. [2][3][4][5][6] These agents are shown to induce the accumlation of DNA-topo II cleavable complex (cleavable complex) which causes tumor cell death. 7)Etoposide (1), an extensively used clinical topo II inhibitor elicits significant antitumor activity against a wide variety of neoplasms, including germ cell malignancies, small cell lung cancer (SCLC), non-Hodgkin's lymphomas, leukemias, Kaposi's sarcoma, neuroblastoma and soft-tissue sarcomas. 2,3)Use of etoposide and cisplatin (or carboplatin) is the standard therapy for patients with SCLC. 4) Doxorubicin is a topo II inhibitor with various activities such as nuclear helicase inhibitory activity 8) and free-radical formation activity. 9) Doxorubicin is a primary drug for the treatment of patients with lymphomas, breast cancer and sarcomas. ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and CHOP (cyclophosphamide, doxorubicin and prednisone) are used as the standard therapy for advanced Hodgkin's lymphoma and intermediate-grade non-Hodgkin's lymphoma, respectively. 5,6) However, these drugs are not used as therapeutics for commonly occurring solid tumors such as non-small-cell lung cancer (NSCLC), colon cancer, gastric cancer and pancreatic cancer.Continuous effort is being made to apply topo II inhibitors for the treatment of various solid tumors. Amurubicin, 10,11) launched on the market in Japan in 2002, shows efficacy against NSCLC and SCLC. Several topo II inhibitors are currently under clinical studies against solid tumors. 12-14)Amonafide (3), 15) which is the basis of our drug design in this program, is also a topo II inhibitor on which intensive clinical studies were conducted in the mid 1990s. In 2003, a phase study was launched in the United States to evaluate amonafide as a potential therapeutic for solid tumors. 16)The objective of our study is to create a structurally novel topo II inhibitor effective against various solid tumors such as NSCLC, colon, gastric and pancreatic cancers. This paper describes our medicinal chemistry program which leads to the discovery of a novel pyrimidocarbazole compound 26 (ER37326) with high in vitro and in vivo potencies. ChemistryThe structures of synthesized compounds for biological evaluation are presented in Table 1. The synthesis of pyrimidoacridones 6-10 is summarized in Chart 1. The amides 30a-c were prepared from corresponding 9-oxoacridan-4-carboxylic acids 29a-c. 17,18) Compounds 29a-c were treated with N,NЈ-carbodiimidazole (CDI) in dimethylformamide (DMF) followed by N,N-dimethylethylenediamine to Co. Ltd.; 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Received March 10, 2004 accepted June 23, 2004; published

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“…6 DNA intercalating ability and antitumor activity resides in a wide variety of chemical entities. Especially, imide derivative compounds have been reported as a potential class of antitumor agents containing amonafide 1, mitonafide 2, azonafide 3 [7][8][9] ( Figure 1) and so on. Encouraged by this result, a group of photosensitizers featuring a chlorin ring system fused to a six-membered cyclic imide structure with a basic N-substituent has received considerable attention.…”

Section: Introductionmentioning

confidence: 99%

Efficient Synthesis and in vitro PDT Effect of Purpurin-18-N-Aminoimides

Cui¹,

Li³

et al. 2010

Bulletin of the Korean Chemical Society

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A simple and efficient synthetic route for making purpurin-18-N-aminoimides is described. The purpurin-18-Naminoimides are obtained by treatment of purpurin-18 methyl ester with various amines. These new compounds have long wavelength absorptions in the range of 706 -711 nm. In preliminary screening, the purpurin-18-N-aminoimides have shown promising photosensitizing activity for the cancer cell by in vitro study in photodynamic therapy.

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2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent

Cited by 57 publications

References 13 publications

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Synthesis and Evaluation of Novel Pyrimido-Acridone, -Phenoxadine, and -Carbazole as Topoisomerase II Inhibitors

Efficient Synthesis and in vitro PDT Effect of Purpurin-18-N-Aminoimides

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