Klavuzon is a naphthalen-1-yl substituted alpha,beta-unsaturated delta-lactone derivative, and is one of the antiproliferative members of this class of compounds. Asymmetric and racemic syntheses of novel alpha,beta unsaturated delta-lactone derivatives are important to investigate their potential for the treatment of cancer. In this study, asymmetric and racemic syntheses of heteroatom-substituted klavuzon derivatives are reported. The syntheses were completed by a well-known three-step procedure. Anti-proliferative activity of seven novel racemic klavuzon derivatives were reported against MCF-7, PC3, HCT116 p53+/+ and HCT116 p53-/- cancer cell lines. Topoisomerase I inhibitory properties of 5,6-dihydro-2H-pyran-2-one derivatives were also studied. (C) 2017 Elsevier Inc. All rights reserved.