Biomedical subjects

B Gatto

Publications and source records attributed to B Gatto.

24 records · Page 2Linked to original sources

PubMed1996

Coralyne and related compounds as mammalian topoisomerase I and topoisomerase II poisons.

DNA topoisomerases are nuclear enzymes responsible for modifying the topological state of DNA. The development of agents capable of poisoning topoisomerases has proved to be an attractive approach in the search for novel cancer chemotherapeutics. Coralyne, an antileukemic alkaloid, has appreciable structural similarity to the potent topoisomerase I and II poison, nitidine. Analogues of coralyne were synthesized and evaluated for their activity as topoisomerase I and topoisomerase II poisons. These analogues were also evaluated for cytotoxicity in the human lymphoblast cell line, RPMI 8402, and its camptothecin-resistant variant, CPT-K5. The pharmacological activity of these analogues exhibited a strong dependence on the substitution pattern and the nature of substituents. Several 1-benzylisoquinolines and 3-phenylisoquinolines were also synthesized. These compounds, which incorporate only a portion of the ring structure of coralyne, were evaluated as topoisomerase poisons and for cytotoxicity. These structure-activity studies indicate that the structural rigidity associated with the coralyne ring system may be critical for pharmacological activity. The presence of a 3,4-methylenedioxy substituent on these coralyne analogues was generally associated with enhanced activity as a topoisomerase poison. 5,6-Dihydro-3,4-methylenedioxy-10,11-dimethoxydibenzo[a,g]quinoliz inium chloride was the most potent topoisomerase I poison among the coralyne analogues evaluated, having similar activity to camptothecin. This analogue also possessed exceptional potency as a topoisomerase II poison. Despite the pronounced activity of several of these coralyne derivatives as topoisomerase I poisons, none of these compounds had cytotoxic activity similar to camptothecin. Possible differences in cellular absorption between these coralyne analogs, which possess a quaternary ammonium group, and camptothecin may be responsible for the differences observed in their relative cytotoxicity.

Antineoplastic Agents↗

PubMed1995

Synthesis and evaluation of terbenzimidazoles as topoisomerase I inhibitors.

The synthesis and pharmacological activity of a series of terbenzimidazoles are described. The ability of these derivatives to induce DNA cleavage in the presence of topoisomerase I was evaluated in vitro. These analogs were also assayed for their cytotoxicity in RPMI 8402 cells and the camptothecin-resistant CPT-K5 cells. In addition the potential for these compounds to serve as substrates for MDR1 was also determined. Several terbenzimidazoles exhibited similar cytotoxicity against variants of human tumor cells that either overexpress MDR1 or are camptothecin-resistant.

Animals↗

PubMed1993

DNA minor groove-binding ligands: a different class of mammalian DNA topoisomerase I inhibitors.

A number of DNA minor groove-binding ligands (MGBLs) are known to exhibit antitumor and antimicrobial activities. We show that DNA topoisomerase (Topo) I may be a pharmacological target of MGBLs. In the presence of calf thymus Topo I, MGBLs induced limited but highly specific single-strand DNA breaks. The 3' ends of the broken DNA strands are covalently linked to Topo I polypeptides. Protein-linked DNA breaks are readily reversed by a brief heating to 65 degrees C or the addition of 0.5 M NaCl. These results suggest that MGBLs, like camptothecin, abort Topo I reactions by trapping reversible cleavable complexes. The sites of cleavage induced by MGBLs are distinctly different from those induced by camptothecin. Two of the major cleavage sites have been sequenced and shown to be highly A + T-rich, suggesting the possible involvement of a Topo I-drug-DNA ternary complex at the sites of cleavage. Different MGBLs also exhibit varying efficiency in inducing Topo I-cleavable complexes, and the order of efficiency is as follows: Hoechst 33342 and 33258 >> distamycin A > berenil > netropsin. The lack of correlation between DNA binding and cleavage efficiency suggest that, in addition to binding to the minor grooves of DNA, MGBLs must also interact with Topo I in trapping Topo I-cleavable complexes.

Animals↗

PubMed1993

On the mechanism of action of quinolone drugs.

Antibacterial quinolones are thought to inhibit DNA gyrase by trapping the enzyme as a complex with the DNA substrate. The precise molecular details of drug-DNA and drug-enzyme interactions remain controversial. Here, a model is proposed that accounts for the influence of magnesium ions on quinolone-DNA binding.

4-Quinolones↗

PubMed1992

Quinolone binding to DNA is mediated by magnesium ions.

The binding of plasmid DNA to norfloxacin, a quinolone antibacterial agent, was investigated by fluorescence, electrophoretic DNA unwinding, and affinity chromatography techniques. The amount of quinolone bound to DNA was modulated by the concentration of Mg2+. No interaction was evident in the absence of Mg2+ or in the presence of an excess of Mg2+, whereas maximum binding was observed at a Mg2+ concentration of 1-2 mM. The experimental data can be fitted to the formation of three types of Mg adducts: a binary adduct with norfloxacin and Mg2+, a binary adduct with DNA and Mg2+, and a ternary adduct with quinolone, plasmid, and Mg2+. We propose a model for the ternary complex, in which Mg acts as a bridge between the phosphate groups of the nucleic acid and the carbonyl and carboxyl moieties of norfloxacin. Additional stabilization may arise from stacking interactions between the condensed rings of the drug and DNA bases (especially guanine and adenine), which may account for the preference exhibited by quinolones for single-stranded and purine-rich regions of nucleic acids. Other possible biochemical pathways of drug action are suggested by the observation that norfloxacin binds Mg2+ under conditions that are close to physiological.

Chromatography, Affinity↗

PubMedDate not supplied

Biologics targeted at TNF: design, production and challenges.

Several biotech-derived drugs aimed at Tumor Necrosis Factor (TNF) have been licensed in the last years, profoundly changing the therapy of several autoimmune diseases based on inflammation, affecting the life of patients and bringing to the market attention the growth potentials of biologics directed at cytokines. The proof of principles that led to the design of these compounds dates back from the nineties, when the involvement of TNF in rheumatoid arthritis was proved by the ability of specific anti-TNF proteins to modulate the inflammatory response in animal models. Monoclonal antibodies aimed at neutralizing the excess TNF were developed with therapeutic purposes, and a chimeric and a full human antibody are now approved for several clinical indications. The design of soluble receptors able to bind and neutralize human TNF paralleled the development of antibodies as therapeutics, and the clinical success of these drugs was achieved by the clever design of a novel recombinant dimeric protein, consisting of the extracellular portion of human TNF receptor linked to the constant portion of a human immunoglobulin. All approved biologics designed to bind and neutralize TNF were obtained through the power of biotechnological methods: the development of these important biopharmaceutical products, their means of production and the challenges they face will be analyzed here in details.

Adalimumab↗