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Medicinal Chemistry Laboratory (MedChemLab)  

Research group members: Dott. Stefania Villa, Dott. Arianna Gelain

Collaborations: Dott. Fiorella Meneghetti, Dott. Matteo Mori (Ph.D.)

The research group expertize concernes:

  • Design and synthesis of novel molecules endowed with biological activity;
  • Analytical characterization of the synthesized products;
  • Structure-activity relationship studies (SAR);
  • Preparation of new materials inhibiting the biofilm formation.

 

In detail the research activity of the group is focused on the following topics:

1. Design and synthesis of potential antiproliferative agents [1], in particular STATs (Signal Transduction and Activators of Transcription) inhibitors, as antitumor agents

STATs are cytosolic proteins and their activated forms are able to transduce extracellular signals from the membrane to the nucleus. These proteins are over-expressed in a great number of tumours. Since STAT3 selectively cause apoptosis in tumour cells, it represents an efficient target for the treatment of cancer. In details our studies are ongoing on:
a) 1,2,5-oxadiazole derivatives [2]
b) benzothiadiazole derivatives

In collaboration with the University of Shizuoka (Shizuoka, Japan) and the University of Padua.

structure of STAT3 dimer


Structure of STAT3 dimer

[1] A. Gelain, M. Mori, F. Meneghetti, F. Porta, L. Basile, G. Marverti, A. Asai, M. Hyeraci, A.N. Garcia-Argaez, L. Dalla Via, S. Guccione, S. Villa,” Exploring the biological activity of a library of 1,2,5-oxadiazole derivatives endowed with antiproliferative activity”, - Anticancer Research, 2019, 39,1, 135-144

[2] F. Porta, G. Facchetti, N. Ferri, A. Gelain, F. Meneghetti, S. Villa, D. Barlocco, D. Masciocchi, A. Asai, N. Miyoshi, S. Marchianò, B.-M. Kwon, Y. Jin, V. Gandin, C. Marzano, I. Rimoldi.“An in vivo active 1,2,5-oxadiazole Pt(II) complex: a promising anticancer agent endowed with STAT3 inhibitory properties”. Eur. J. Med. Chem. 2017, 131:196-206.

2. Design and synthesis of potential antitubercolar agents endowed with innovative targets

Among the evaluated targets:

  • MbtI is an enzyme (salicylate synthase) that catalyzes the first step of mycobactines synthesis. These siderophores play an important role in iron acquisition, that is essential for Mycobacterium tuberculosis growth into the macrophages. Therefore MbtI is a selective target for the synthesized furan-based derivatives.
  • MPtpB is a low molecular weight phosphatase  essential for Mtb pathogenesis, suggesting that it may represent new and valid pharmaceutical target for the treatment of TB.

In collaboration with the Universities of Pavia and Pisa.

L.R. Chiarelli, M. Mori, D. Barlocco, G. Beretta, A. Gelain, E. Pini, M. Porcino, G. Mori, G. Stelitano, L. Costantino, M. Lapillo, D. Bonanni, G. Poli, T. Tuccinardi, S. Villa, F. Meneghetti. “Discovery and Development of Novel Salicylate Synthase (MbtI) Furanic Inhibitors as Antitubercular Agents” - Eur. J. Med. Chem. 2018, 155, 754-763.

3. Studies on potential antimalarial agents

The aim of the project is the identification of novel antimalarial agents targeting the Atg8-Atg3 complex, involved in autophagia and responsible for the entrance of Plasmodium falciparum into the red blood cells. The synthesized peptidomimetics have shown an interesting PPI (protein-protein interaction) inhibition.

In collaboration with Prof. G. Grazioso and Prof. Donatella Taramelli of University of Milan and the Case Western Reserve University School of Medicine (Cleveland, USA).

S. Villa, L. Legnani, D. Colombo, A. Gelain, C. Lammi, D. Bongiorno, D.P. Ilboudo,  K.E. McGee, J. Bosch,  G. Grazioso.  “Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors”J. Comput. Aided Mol. Des., 2018, 32 (3), 473-486.

4. Novel materials based on biofunctionalized surfaces with antifouling activity

Natural substances endowed with antibacterical activity (cinnamic and salicylic acids) have been properly derivatized to covalently functionalize:

- polymeric matrix (e.g. LDPE, low density polyethylene) with the aim to obtain new materials for medical devices (Anfomat project funded by Fondazione Cariplo)

S. Dell'orto, C. Cattò, F. Villa, F. Forlani, E. Vassallo, M. Morra, F. Cappitelli, S.Villa,  A. Gelain, “Low density polyethylene functionalized with antibiofilm compounds inhibits Escherichia coli cell adhesion” - Journal of Biomedical Materials Research -Part A2017, 105, 3251-3261.

- nanoparticles (e.g. Ludox H40) to prepare new materials inhibiting bacterical/fungal biofilm formation.

In collaboration with Prof. F. Cappitelli, Dr. F. Villa of University of Milan and the University of Wollongong (Australia).

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