Functionalization of Hydroxylated Phenols and Biphenols Bearing an a,b-Unsaturated Keton as Lead Compound

The unique pharmacophore structure of hydroxylated biphenyls has a crucial role in the biological activity of many natural occurring compounds This structural feature allows the activation of a large and selective number of interactions with the surface of several proteins. Recently, our group has prepared an analogue of curcumin 1 (biphenol 2) We found that compound 2 was an effective breaking-chain activator in bulk lipid autoxidation , showed strong cytotoxicity against rat pheochromocytoma (PC12) cells, a slow-growing neuroendocrine tumoral cells and interacts with high affinity with alpha-synuclein . When Ph-OH groups are OMe protected, antiproliferative and proapoptotic activities against malignant melanoma and neuroblastoma were found [3a-c]. Biphenol 2 and its monomer 3 share many pharmacological features with curcumin 1 and, conversely to 1, compounds 2 and 3 are stable in organic and aqueous solutions. With the aim of searching for new compounds with enhanced biological activities, in the present study, we prepared a collection of derivatives of compound 2 and of monomeric equivalent 3. All new prepared compounds possess a common ?,?-unsaturated ketone moiety bearing a hydroxylated biphenyl or phenyl structure with Ph-OH group substituted with functionalities with different features (i.e. groups able to increase or decrease lipophilicity of the molecule) The new compounds were prepared through straightforward synthetic procedures. Different functional groups were introduced giving ether, ester, carbonate, sugar and acetal derivatives that influenced the physico-chemical properties of the molecule. The antiproliferative capacity of all the prepared compounds was preliminarly calculated.