Synthesis and cytotoxic activity of a new potential DNA bisintercalator: 1,4-Bis{3-[N-(4-chlorobenzo[g]phthalazin-1-yl)aminopropyl]}piperazine. 2010

Juan Galisteo, and Pilar Navarro, and Lucrecia Campayo, and María J R Yunta, and Fernando Gómez-Contreras, and Janny A Villa-Pulgarin, and Beatriz G Sierra, and Faustino Mollinedo, and Jorge Gonzalez, and Enrique Garcia-España
Instituto de Química Médica, Centro de Química Orgánica Manuel Lora-Tamayo, CSIC, c/Juan de la Cierva 3, E-28006 Madrid, Spain.

The synthesis of new 1,4-bisalkylamino (2-4) and 1-alkylamino-4-chloro (5-6) substituted benzo[g]phthalazines is reported. Compounds 2-4 and 6 were prepared both in the free and heteroaromatic ring protonated forms. Bifunctional 6 contains the 1,4-bisaminopropylpiperazine chain as a linker between the two heteroaromatic units, whereas 5 is its monofunctional analogue. The in vitro antitumour activity of the synthesized compounds has been tested against human colon, breast and lung carcinoma cells, and also against human glioblastoma cells. Results obtained show that all of them are active in all cases, but bifunctional 6.2HCl is remarkably effective against the four cell lines tested, exhibiting IC50 values in the range of 10(-7) M, similar to those found for doxorubicin. The bifunctional structure of 6.2HCl enhances activity with respect to the monofunctional related compounds 5 and 7, leading to the highest activity among all the compounds tested. Molecular modelling of 6 suggests that those results could be indicative of DNA bisintercalation, which should be specially favoured in the diprotonated form 6.2HCl, a compound suitable for being studied more in depth in further biological tests. Measure of the DNA thermal melting curves show that the linear rise in Tm for bifunctional 6.2HCl is nearly twice than that one obtained for monofunctional 5, and supports the DNA-binding hypothesis.

UI MeSH Term Description Entries
D007364 Intercalating Agents Agents that are capable of inserting themselves between the successive bases in DNA, thus kinking, uncoiling or otherwise deforming it and therefore preventing its proper functioning. They are used in the study of DNA. Intercalating Agent,Intercalating Ligand,Intercalative Compound,Intercalator,Intercalators,Intercalating Ligands,Intercalative Compounds,Agent, Intercalating,Agents, Intercalating,Compound, Intercalative,Compounds, Intercalative,Ligand, Intercalating,Ligands, Intercalating
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009369 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D009691 Nucleic Acid Denaturation Disruption of the secondary structure of nucleic acids by heat, extreme pH or chemical treatment. Double strand DNA is "melted" by dissociation of the non-covalent hydrogen bonds and hydrophobic interactions. Denatured DNA appears to be a single-stranded flexible structure. The effects of denaturation on RNA are similar though less pronounced and largely reversible. DNA Denaturation,DNA Melting,RNA Denaturation,Acid Denaturation, Nucleic,Denaturation, DNA,Denaturation, Nucleic Acid,Denaturation, RNA,Nucleic Acid Denaturations
D010793 Phthalazines Bicyclic heterocyclic compounds containing a BENZENE ring fused to PYRIDAZINE.
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077489 Piperazine An anti-nematodal agent effective against the intestinal nematodes ASCARIS LUMBRICOIDES (roundworm) and ENTEROBIUS VERMICULARIS (pinworm, threadworm). It produces a neuromuscular block leading to flaccid muscle paralysis in susceptible worms, which are then dislodged from the gut and expelled in feces. 1,4-Diazacyclohexane,1,4-Piperazine,Piperazine Diacetate,Piperazine Dihydrochloride,Piperazine Hexahydrate,Piperazine Hydrate,Piperazine Hydrobromide,Piperazine Hydrochloride,Piperazine Monohydrochloride,Piperazine Phosphate,Piperazine Phosphate (1:1),Piperazine Phosphate Anhydrous,Piperazine Salt,Piperazine Sulfate,Piperazine Tartrate,Piperazine Tartrate (1:1), (R-(R*,R*))-isomer,Piperazine Tartrate, (R-(R*,R*))-isomer,Piperazinium Oleate,Pripsen,1,4 Diazacyclohexane,1,4 Piperazine

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