Improved synthesis of MC4-PPEA and the biological evaluation of its hydroxymethyl derivative

Nicotinamide phosphoribosyltransferase (Nampt) is an intriguing target for the treatment of many diseases, including cancer. Previously, our group demonstrated that carborane clusters may be used to increase the potency of small molecule inhibitors of Nampt over other, similarly sized organic moieties. Herein, we report a greatly improved, gram-scale synthesis of our most potent agent: 1-(4'-(trans-3″-(3‴-pyridyl) acrylamide)butyl)-1,7-dicarba-closo-dodecaborane (MC4-PPEA). Additionally, the carborane moiety of the molecule has been modified with a hydroxymethyl functional group to allow for its covalent attachment to targeted prodrugs, the synthesis of which are underway. Using cell viability assays, we demonstrate that this new derivative exhibits low, to mid-nanomolar potencies against human breast cancer cell lines in vitro.