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Alberto Leoni

Associate Professor

Department of Pharmacy and Biotechnology

Academic discipline: CHIM/08 Pharmaceutical Chemistry


Keywords: Study of the structure-activity relationships Study of the mechanism of action Evaluation of the antitumor activity Synthesis of new molecules

The main research line is devoted to the development of antitumor agents belonging to the following classes: imidazothiazole guanylhydrazones, indolylmethylene-2-indolinones and imidazothiazolylmethylene-2-indolinones; moreover substituted indolinones have been condensed, through a methine bridge, with a trimethoxyphenyl group which is present in well known antitumor drugs such as combretastatin, podophyllotoxin and colchicine. Even the synthesis of bis-indole derivatives has been considered which led to file a patent. The great majority of the published compounds showed an interesting activity with 50% growth inhibition values of 10-7 and 10-8 M and low toxicity. The antitumor activity was evaluated in agreement with the protocols available at the National Cancer Institute (NCI, Bethesda, MD) on a panel of 60 human cell lines. The most interesting compounds were studied by means of flow cytometry on cell growth and cell cycle progression in colon adenocarcinoma HT29 cell lines and on ovarian carcinoma IGROV-1 cells. These tests demonstrated that compounds showing low toxicity may interfere with cell cycle progression with a block in G2/M without a significant effect on tubulin polymerization whereas other derivatives seem to trigger a different and not yet identified biochemical pathway. Several compounds led to apoptosis as shown by caspase activation at least in ovarian carcinoma cells. These observations suggest that the test compounds could interfere with cell proliferation by means of multiple mechanisms.

Currently there is interest in discovering and developing small molecules capable of binding to DNA in a highly sequence-selective manner, as the ability to target and then down-regulate individual genes has potential in the therapy of genetic based diseases (e.g., cancer), diagnostics, functional genomics, and target validation. The pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics (PBDs) are a well-known class of sequence-selective DNA-binding agents derived from Streptomyces species. Their precise mode of interaction with DNA is unique and has been extensively studied; they bind within the minor groove of DNA There has been a considerable effort by a number of groups to develop new synthetic routes to the PBD ring system. However, due mainly to the difficulties associated with synthesizing useful quantities of PBD analogues, little work regarding structure-activity relationships (SAR) has been published. We report the results of an investigation into the effect of modifying substitution pattern of the aromatic A-ring and of conversion of the aromatic A-ring of the PBD system into a pyrazole on both DNA-binding reactivity and cytotoxic potency.

Since the COX2 selective antiinflammatory agents used in therapy show undesired side effects limiting their use, the search of safer molecules is still active. In this context we synthesised and evaluated the inhibitory activity of a series of N-benzyl-2-chloroindol-3-carboxylic acids. Some derivatives showed inhibitory activity similar to that of rofecoxib.

Mitochondrial NADH-Coenzyme Q (CoQ, ubiquinone) oxidoreductase (EC, complex I) is the most complicated and the least understood of the respiratory chain complexes. Despite recent progress in structural studies, there is no structural information about complex I comparable with the crystallographic data available for other respiratory complexes. This lack of information is principally due to the complexity of the system. In the last decades, the interest in this NADH-ubiquinone reductase is increasing, due to its possible involvement in the pathogenesis of human neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, in diabetes and in aging. We describe the synthesis of a series of imidazo[2,1-b]thiazoles and 2,3-dihydroimidazo[2,1-b]thiazoles connected by means of a methylene bridge to CoQ0. These compounds were tested as specific inhibitors of the NADH:ubiquinone reductase activity in mitochondrial membranes

A class of drugs used for the therapy of Alzheimer's disease act as acetylcholinesterase inhibitors. The presence of a peripheral site of the enzime, besides the catalytic site, and the binding to both the sites given by bisquaternary compounds, led us to design and prepare compounds containing two imidazothiazole systems, separated by different spacers. From some of them even the bisammonium salts were prepared. The inhibitory activity was studied with a chemiluminescent method.

Due to their important functions, voltage-gated Ca2+ channels have been extensively studied and different drugs are available that are known to interact with them. L-type calcium channel blockers have gained a critical role in the treatment of different cardiovascular pathologies. The 1,4-DHP nucleus appears to be an interesting structure interacting with a wide variety of channel and receptors and is an example of a "privileged structure": a core structure that by appropriate molecular decoration can be directed to diverse pharmacological tissues. We reported the synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-heteroaryl-1,4-dihydropyridines.

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