Convergent Total Synthesis of PM742 and SAR-Guided Development of the Clinical Candidate PM534

We report the first total synthesis of PM742 using N-Boc-D-Norvaline and 2-Methyl-L-Cysteine hydrochloride as starting materials in a convergent sequence of eight chemical steps. This strategy provides efficient access to PM742 and enables the preparation of structurally related analogs. PM742 exhibited in vitro cytotoxic activity against a panel of human tumor cell lines, which prompted preliminary structure-activity relationship (SAR) studies. These efforts led to the preparation of PM534, a related analog with improved activity that has now entered Phase I clinical trials in humans.