Introduction

The [1,2]oxazole is attractive scaffold in medicinal chemistry being the core structure of many drug candidates. We had previous excellent results in preclinical studies with a class of compounds containing the  [1,2]oxazole core, with potent in vitro and in vivo antitumor activity. Thus, we modified the original structure, by synthesising the pyrrolocyclohepta oxazoles. Some derivatives showed potent antitumor activity on the NCI panel with GI50 reaching the nanomolar level.

Technical features

We have synthesised a series of new compounds having the pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazole structure, and their use for the treatment of pathologies having hyperproliferative features included those having neoplastic nature. The new compounds screened at the NCI of Bethesda on a panel of 60 human cell lines divided into 9 subpanels (breast, ovaries, lung, colon, CNS, melanoma, leukemia, renal, prostate), showed remarkable growth inhibitory activity  (GI50) from micro to nanomolar, disclosing 10p and 10q as very promising derivatives.  In particular, these two most active compounds, bearing at least a 3,5-dimethoxy benzyl moiety at the pyrrole nitrogen showed mean graph mid-points (MG_MID) of  0.08 and 0.20 µM respectively.

Possible Applications

• Hyperproliferative disorders including cancer.

Advantages

• New chemical structures: no examples exist in the literature so far;
• Versatile and innovative synthetic procedure, thus easy chemical manipulation of lead structures;
• Remarkable antiproliferative effect.