Michael Acceptor Bearing A Hydroxylated Biphenyl Structure As Molecular Core For New Compounds Against Malignant Melanoma Cells

Cutaneous malignant melanoma is the most lethal form of skin cancer that arises from uncontrolled proliferation of melanocytes that are cells producing pigments. Curcumin, the main component of Curcuma longa, contains an ?,?-unsaturated Michael acceptor pharmacophore that is well recognised in the design of new antimelanoma drugs in virtue of the emerging role of this moiety in interacting with nucleophiles present in the cancer cells1. Curcumin exhibits also remarkable anti-oxidant, anti-inflammatory and neuroprotective activities. Recently, our group has prepared an analogue of curcumin, compound 1, that showed antiproliferative and proapoptotic activities against malignant melanoma and neuroblastoma ten times stronger than those of curcumin2. The interesting result achieved with compound 1, encouraged us to pursue further structural tuning in order to discover more efficient drug candidates. Hydroxylated biphenyl unit is embedded in many structures of bioactive natural products and provides an ideal molecular framework for structural modifications in the development of drug candidates. A small collection of C2-symmetry hydroxylated biphenyls featured with a ?,?-unsaturated ketone (Michael acceptor) as lead structure was prepared and the capability to act against different human malignant melanoma cell lines was assayed. The antiproliferative capacity of each compound was calculated as 50% inhibition concentration (IC50) that improved down to 1.2 ?M after 72 h of treatment. The prodrug approach was applied in the synthesis of the compounds in order to improve delivery of compounds into the cell by modulation of Ph-OH protective group. Different functional groups that influenced the physicochemical properties of the molecule were introduced, mainly its lipophilicity and the capacity of hydrolysis into the cell. The effective role of the hydroxylated biphenyl structure in inhibiting growth of malignant melanoma cells was clearly evidenced.