Medicinal Chemistry - Synthesis. Coordinator: Leoni

Design and synthesis of small molecules able to interact with molecular targets or biological systems of therapeutic or biological interest, mainly involved in anticancer/antitumor therapy

Research themes

The research activity is mainly focused on the design and synthesis of small molecules as potential anticancer/antitumor agents. The main research topics are: (i) synthesis of tubulin ligands; (ii) synthesis of compounds able to interfere with the mitochondrial respiratory chain; (iii) synthesis of G-quadruplex ligands. From a chemical point of view, the compounds are guanylhydrazones with an imidazothiazole or diimidazopyrimidine nucleus, indolylmethylene-2-indolinones, imidazothiazolylmethylene-2-indolinones, and bis-indoles derivatives. Firstly, the evaluation of anti-proliferative activity is carried out in collaboration with the National Cancer Institute (Bethesda, MD) on a panel of 60 human cancer cell lines. Based on the activity profile, the compounds may be selected for further studies and eventually tested in vivo. In particular, the action on the cell cycle and the possible induction of apoptosis in different tumor lines, as well as the effect on the polymerization of tubulin are studied in collaboration with Dr. Ernest Hamel (National Cancer Institute at Frederick, MD).

The glucose uptake and glycolysis process are increased in many types of cancers, as a response to the activation of oncogenes (RAS and MIK) and the mutation of tumor suppressor genes (eg. TP53). Both the RAS product and hypoxia can independently increase the levels of the transcription factors HIF1-α and HIF2-α, responsible for the glycolysis increase. The effects of new small molecules on these transcription factors are studied in collaboration with Prof. ssa Porcelli (University of Bologna), in order to identify new leads for the development of potential anticancer agents.

G-quadruplexes (G4s) are DNA secondary structures formed by G-rich sequences which have been identified in critical position of human genome, such as telomeres and promoters. Their involvement in numerous events related to tumor development makes the G4s promising targets for the development of selective anticancer agents. The study of new G4s ligands mainly concerns hydrazone derivatives with a diimidazopyrimidine nucleus capable to strongly stabilize these structures, selectively with respect to duplex DNA, and highlighting preferential interactions for parallel G4s. The biophysical studies of binding interactions with telomeric or promoter G4s are carried out in collaboration with Prof. Randazzo (University of Naples Federico II), whereas the effects of G4 binders on cancer cell lines are studied in collaboration with Prof. Capranico (University of Bologna).

Lab members

Prof. A. Leoni
Prof. A. Locatelli
Prof. R. Morigi

Internship projects

Internship projects (6) concern the development of research themes.

Main publications

Amato J, Morigi R., Pagano B., Pagano A., Ohnmacht S., De Magis A., Tiang Y-P., Capranico G., Locatelli A., Graziadio A., Leoni A., Rambaldi M., Novellino E., Neidle S., Randazzo A. “Toward the Development of Specific G‑Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives.” J. Med. Chem. 59: 5706-5720 (2016).

Morigi R, Locatelli A, Leoni A, Rambaldi M, Bortolozzi R, Mattiuzzo E, Ronca R, Maccarinelli F, Hamel E, Bai R, Brancale A, Viola G.: Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents. Eur.J.Med.Chem. 166, 514-530 (2019).

Conti I, Morigi R, Locatelli A, Rambaldi M, Bua G, Gallinella G, Leoni A.: Synthesis of 3-(Imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one derivatives and study of their antiviral activity against parvovirus B19. Molecules 24 (6), 1-15 (2019).

Locatelli A, Iommarini L, Graziadio A, Leoni A, Porcelli A.M, Iotti S, Malucelli E, Francia F, Venturoli G, Farruggia G.: Dansyl acetyl trehalose: a novel tool to investigate the cellular fate of trehalose. RSC Advances 9, 15350-15356 (2019).

Amato J, Miglietta G, Morigi R, Iaccarino N, Locatelli A, Leoni A, Novellino E, Pagano B, Capranico G, Randazzo A. (2020) “Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells” J Med Chem. 63(6): 3090-3103. DOI: 10.1021/acs.jmedchem.9b01866

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