Introduction

Diffuse malignant peritoneal mesothelioma (DMPM), is an aggressive,  rapidly lethal tumor, poorly responsive to conventional therapeutic strategies. Infact palliative surgery, systemic/intraperitoneal chemotherapy and abdominal irradiation showed to be ineffective, with a median survival of about one year. Thus requiring new compounds. We have discovered a class of small molecules, having [1,2]oxazolo fused tricyclic structure.

Technical features

The most active compounds inhibited tumor cell proliferation at nanomolar concentrations against the NCI panel of 60 human tumor cell lines, reduced in vitro and in vivo cell growth and induced apoptosis, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), as a consequence of the inhibition of tubulin polymerization, in a vinca alkaloid-like manner making it as a new lead for the discovery of new potent antimitotic drugs. Notably, our compounds were selective against malignant cells. The in vivo antitumor activity in STO cells following subcutaneous xenotransplantation into athymic nude mice by intraperitoneal administration determined a statistical significant (P<0.05) tumor growth delay compared to control mice, with a maximum tumor volume inhibition up to 60%. The new compounds were well tolerated with minimal weight loss and no toxic deaths.

Possible Applications

• Treatment of rare tumor DMPM;
• Treatment of hyperproliferative diseases including cancer;
• Possible therapeutic potential of these compounds.

Advantages

• High yielding and easily scalable synthetic process;
• Low molecular weight compound;
• Remarkable antiproliferative effects;
• High selectivity towards cancer cells and experimental models of DMPM;
• High tolerability.