Abstract: The present invention relates to novel SMAC mimetic peptidomimetics useful for the treatment of proliferative diseases including cancer in mammals The novel SMAC mimetics are prepared by incorporating (2S,5R)-5-(5-methylfuran-2-yl)pyrrolidine-2-carboxylic acid, a novel unnatural amino acid that imparts exclusively trans amide bond geometry favourable for target protein binding. Here, the novel SMAC mimetic molecule(s) not only show its efficacy in varied cancer types but also demonstrate in vitro and in vivo efficacy against therapy resistant cancer as a single agent. The novel SMAC mimetics disclosed in the present invention binds to BIR-2 and BIR-3 domains of the XIAP and exhibit high anti-proliferative activity against variety of mammalian cancer cell lines that include but not limited to chemotherapy and TRAIL resistant cell lines.