mitonafide and amonafide

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Morpholines; Structure-Activity Relationship

The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA.. To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity.. The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines.. Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide.. The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.

Topics: Adenine; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Naphthalimides; Organophosphonates; Structure-Activity Relationship; Topoisomerase II Inhibitors

Amonafide (1), a naphthalimide which binds to DNA by intercalation and poisons topoisomerase IIalpha, has demonstrated activity in phase II breast cancer trials, but has failed thus far to enter clinical phase III because of dose-limiting bone marrow toxicity. Compound 17 (one of 41 new compounds synthesized) is a novel anticancer naphthalimide with a distinct mechanism of action, notably inducing autophagy and senescence in cancer cells. Compound 17 (2,2,2-trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157)) was found to have a 3-4-fold higher maximum tolerated dose compared to amonafide and not to provoke hematotoxicity in mice at doses that display significant antitumor effects. Furthermore, 17 has shown itself to be superior to amonafide in vivo in models of (i) L1210 murine leukemia, (ii) MXT-HI murine mammary adenocarcinoma, and (iii) orthotopic models of human A549 NSCLC and BxPC3 pancreatic cancer. Compound 17, therefore, merits further investigation as a potential anticancer agent.

Topics: Acetamides; Adenine; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Camptothecin; Cell Line, Tumor; Cellular Senescence; Deoxycytidine; Drug Screening Assays, Antitumor; Erythrocyte Count; Female; Gemcitabine; Humans; Imides; Irinotecan; Isoquinolines; Leukocyte Count; Maximum Tolerated Dose; Mice; Naphthalimides; Neoplasm Transplantation; Organophosphonates; Platelet Count; Structure-Activity Relationship; Topoisomerase I Inhibitors; Urea

New benz[d,e]isoquinoline-1,3-diones related to mitonafide (CAS 54824-17-8) and amonafide (CAS 69408-81-7) with double substitution on the chromophore and branched side chains have been synthesized and their biological activity determined. Molecular modeling studies of 3a based on X-ray crystallographic data of mitonafide have shown that the aromatic system intercalates between GC steps of DNA. The in vitro cytotoxic test data using CX-1 and LX-1 cells showed higher cytotoxic activities in disubstituted derivatives compared to both lead compounds. Some of the compounds have been selected for in vivo test using L1210 tumor cells and CX-1 cells. Two of them (3b and 3j) have shown promising activity as good candidates for clinical development.

Topics: Adenine; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Imides; Isoquinolines; Leukemia L1210; Mice; Mice, Inbred DBA; Models, Molecular; Molecular Conformation; Naphthalimides; Organophosphonates; Tumor Cells, Cultured

A high performance liquid chromatography (HPLC) method for the qualitative and quantitative determination of amonafide (CAS 69408-81-7) and mitonafide (CAS 54824-17-8), two new antineoplastic molecules, in finished pharmaceutical dosage forms (tablets) is developed and validated. The results submitted in this work suggest that HPLC method is linear (range 0.54 microgram to 2.70 micrograms for amonafide, and 1.40 micrograms to 5.25 micrograms for mitonafide), sensitive (discriminator capacity 0.1098 microgram for amonafide and 0.1324 microgram for mitonafide), precise (coefficient of variation < or = 2.39% within run, < or = 1.18% between run for tablets with amonafide, and < or = 1.38% within run and < or = 0.96% between run for tablets with mitonafide), accurate (mean recovery 97.55, 98.85, 98.905% for the three different kinds of tablets with amonafide, and 100.73, 101.54% for the two types of tablets with mitonafide) and selective, even when degradation products are present. The volume of extractor liquid must be specially taken into account with regard to the accuracy of the method, because drug extraction can be influenced by the nature of the excipients.

Topics: Adenine; Antineoplastic Agents; Chromatography, High Pressure Liquid; Excipients; Imides; Isoquinolines; Naphthalimides; Organophosphonates; Regression Analysis; Tablets

A series of bis-intercalators bearing the 1,8-naphthalimide chromophore has been synthesized and in vitro activities determined. Most compounds have higher activities in HT-29 than the leader compounds Mitonafide and Amonafide. One of them (22) was selected for in vivo studies and presents an interesting activity in MX-1 and OVCAR models. (22) also acts as antitopoisomerase II.

Topics: Adenine; Animals; Antineoplastic Agents; Humans; Imides; Intercalating Agents; Isoquinolines; Mice; Naphthalenes; Naphthalimides; Neoplasms, Experimental; Organophosphonates; Structure-Activity Relationship; Tumor Cells, Cultured

A study was done on the factors which could modify the oral bioavailability of two new cytotoxic molecules (mitonafide and 2HCl amonafide) when administered in solid form. From the values of the ionization constants, we can assume that the absorption of these drugs is produced in the first segments of the small intestine. In the course of both molecules through the digestive tract to the site of absorption, we presume that their chemical stability will not be significantly compromised by the influence of pH of the GI tract. The high aqueous solubility of 2HCl amonafide and the rapid dissolution rate of mitonafide at low pH values lead to assume that the previous dissolution of the drugs will not be an essential factor in the absorption of the oral form.

Topics: Adenine; Antineoplastic Agents; Biological Availability; Hydrogen-Ion Concentration; Imides; Intercalating Agents; Isoquinolines; Naphthalimides; Organophosphonates; Solubility

Treatment of SV40-infected monkey cells with amonafide (benzisoquinolinedione), an intercalative antitumor drug, resulted in rapid accumulation of linearized intracellular SV40 DNA molecules that were protein linked. Studies using purified mammalian DNA topoisomerase II have shown that amonafide and its structural analogs interfere with the breakage-rejoining reaction of the enzyme by stabilizing a reversible enzyme-DNA "cleavable complex." Denaturation of the cleavable complex with sodium dodecyl sulfate resulted in DNA cleavage and the covalent association of topoisomerase II polypeptides with the cleaved DNA. Unwinding measurements indicate that amonafide is a DNA intercalator. These results suggest that amonafide and its structural analogs (e.g., mitonafide) represent a new class of intercalative topoisomerase II-active antitumor drugs. Different from other topoisomerase II-active antitumor drugs, amonafide and mitonafide induce specific DNA cleavage at a single major site on pBR322 DNA. The strong site specificity of amonafide may allow detailed characterization of the intercalator-stabilized, topoisomerase II-DNA cleavable complex.

Topics: Adenine; Animals; Cell Line; DNA Damage; DNA Topoisomerases, Type II; DNA, Viral; Haplorhini; Imides; In Vitro Techniques; Intercalating Agents; Isoquinolines; Naphthalimides; Nucleic Acid Conformation; Organophosphonates; Simian virus 40; Structure-Activity Relationship; Topoisomerase II Inhibitors

Several synthetic imide derivatives of naphthalic acid that bind to DNA and have anti-neoplastic properties are studied here in relation to the fluorescence they produce in the chromatin of chicken nucleated red blood cells.

Topics: Adenine; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Chickens; DNA; Fluorescent Dyes; Imides; Isoquinolines; Naphthalimides; Organophosphonates