SYNTHESIS OF ISOXAZOLE DERIVATIVES AS POTENTIAL HDAC INHIBITORS

The incidence of malignancies has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In this regard, the discovery of the rules governing the inhibition of the various histone deacetylase (HDAC) isoforms is likely to be crucial to identify novel anticancer agents that act as epigenetic modulators of gene transcription. Unfortunately, there are no selective HDAC inhibitors approved for clinical use in oncology. Most of them are likely pan-inhibitors towards the different isoforms of the enzyme and may lead to several side-effects. Since the construction of the capping group of the general structure of a standard HDAC inhibitor (Fig. 1) is usually a heterocycle and constitutes a key factor for the successful achievement of selectivity among various HDAC isoforms, we focused our efforts in the synthesis of isoxazole derivatives with different degree of unsaturation by exploiting a straightforward synthetic method carried out in our laboratories that entails the 1,3- dipolar cycloaddition of nitrile oxides and nitrones olefins or alkynes. Afterward, we joined the new capping group to the best chemical features of the HDAC inhibitors reported in literature, i.e. a cinnamoyl linker and a Zn2+ binding moiety such as the hydroxamic acid.