azonafide and amonafide

The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.

Topics: Adenine; Animals; Antineoplastic Agents; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Imides; Intercalating Agents; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Naphthalimides; Neoplasms; Organophosphonates; Tumor Cells, Cultured; Tumor Stem Cell Assay

Three new types of amonafide and azonafide analogues were synthesized and screened in a panel of human solid tumor cells and murine L1210 leukemia cells. The structural types included tetrahydroazonafides, which have the naphthalene chromophore of amonafide within the anthracene nucleus of azonafide; phenanthrene analogues, in which the linear anthracene nucleus is replaced by the bent phenanthrene nucleus; and azaphenanthrenes. The tetrahydroazonafides were generally intermediate in potencies between amonafide and azonafide against the tumor cells, but some of them had high potencies against the L1210 cells and were more potent against the MDR strain than the sensitive strain. The phenanthrene and azaphenanthrene analogues showed no improvement on the potencies of the anthracenes.

Topics: Adenine; Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Humans; Imides; Isoquinolines; Mice; Naphthalimides; Organophosphonates; Phenanthrenes; Structure-Activity Relationship; Tumor Cells, Cultured

Intercalative binding of the antitumor drugs amonafide and azonafide to the oligonucleotide duplex d(GGCCGGCCGG).d(CCGGCCGGCC) was compared using molecular dynamics in vacuum with the AMBER force field. A number of reasonable possible binding conformations were obtained, with the azonafide complexes favored over the amonafide complexes in net binding enthalpy. In comparison with amonafide, the larger chromophore of azonafide permits greater DNA distortion and wider side-chain swings, without falling out of the intercalation site. The best model obtained was used for further dynamics on amonafide and azonafide with solvent and counterions present, and again the azonafide complex had a more favorable enthalpy. Furthermore, the enthalpy change on going from solvent into the intercalation site was less unfavorable for azonafide. These results are consistent with the stronger DNA binding of azonafide compared to amonafide, as observed in relative melting transition temperature increases and tumor inhibition in cell cultures.

Topics: Adenine; Base Sequence; Binding Sites; Calorimetry; Computer Simulation; DNA; Hydrogen Bonding; Imides; Intercalating Agents; Isoquinolines; Molecular Conformation; Molecular Sequence Data; Molecular Structure; Naphthalimides; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Organophosphonates

Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.

Topics: Adenine; Animals; Antineoplastic Agents; Cattle; Colonic Neoplasms; DNA; Doxorubicin; Heart Diseases; Humans; Imides; Isoquinolines; Leukemia P388; Male; Mice; Mice, Inbred DBA; Mitoxantrone; Naphthalimides; Organophosphonates; Structure-Activity Relationship; Tumor Cells, Cultured