Synthesis and Topoisomerase I inhibitory properties of klavuzon derivatives

Abstract

Klavuzon is a naphthalen-1-yl substituted α,β-unsaturated δ-lactone derivative, and is one of the anti-proliferative members of this class of compounds. Asymmetric and racemic syntheses of novel α,β-unsaturated δ-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.

Antiproliferative activity of (R)-4′-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition

“…(R)-4 0 -methylklavuzon was previously synthesized by our group and its cytotoxic effects were demonstrated on prostate, colon, pancreatic, breast, ovary cancer cells [39,41,91,92]. (R)-4 0 -methylklavuzon was also found to irreversibly inhibit topoisomerase I enzyme [39].…”

“…(R)-4 0 -methylklavuzon was previously synthesized by our group and its cytotoxic effects were demonstrated on prostate, colon, pancreatic, breast, ovary cancer cells [39,41,91,92]. (R)-4 0 -methylklavuzon was also found to irreversibly inhibit topoisomerase I enzyme [39]. Topoisomerases which are classified by Topo I and Topo II, are responsible for regulating DNA topology by forming single or double strand breaks, respectively.…”

“…Both drug candidates may act like acrylamide for cysteine residues. Previously, it was found that (R)-goniothalamin ( 1) and (R)-4 0 -methylklavuzon (2) are novel irreversible inhibitors of topoisomerase I [39]. Additionally, immunosuppressive effects of 4 0 -methylklavuzon was shown by inhibition of IL-2 production in T lymphocytes (Jurkat e6-1) with limited cytotoxicity [40].…”

CRM1 inhibitory and antiproliferative activities of novel 4′-alkyl substituted klavuzon derivatives

“…[7][8][9][10][11][12][13][14][15][16] On the other hand, a few number of studies were dedicated to explore the mechanism of action of goniothalamin derivatives such as inhibition of CRM1 nucleocytoplasmic transport receptor protein 17 and inhibition of topoisomerase I. 18 In terms of cell death, it was shown that (R)enantiomer of goniothalamin induces apoptosis while (S)-enantiomer induces autophagy. 19 Efficiency of racemic and enantiomerically pure forms of goniothalamin was also demonstrated in Ehrlich solid tumor in mice.…”

“…1). 18 Multi-target drug discovery gained significant attention in the last decade to overcome the difficulty of curing diseases having complex etiology and drug-resistance issues. 22 In this respect, goniothalamin derivatives can be considered as a dual acting inhibitor because of its capability to inhibit both CRM1 and topoisomerase I.…”