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

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM(+)/CD133(+) cancer stem cells. IC50 of (R)-4'-methylklavuzon was found as 1.25 mu M for HuH-7 parental cells while it was found as 2.50 mu M for HuH-7 EpCAM(+)/CD133(+) cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC50 values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM(+)/CD133(+) cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels. (C) 2019 Elsevier Masson SAS. All rights reserved

Synthesis and Topoisomerase I inhibitory properties of klavuzon derivatives

WOS: 000404534300027PubMed ID: 28242062Klavuzon 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.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [110T782]This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK, 110T782). Antiproliferative effects of the compounds were tested in Biotechnology and Bioengineering Centre Research Laboratory in IZTECH. HPLC analyses were performed Environmental Development Application and Research Center in IZTECH. We are thankful for their support

A Rhodium Nanoparticle-Lewis Acidic Ionic Liquid Catalyst for the Chemoselective Reduction of Heteroarenes

We describe a catalytic system composed of rhodium nanoparticles immobilized in a Lewis acidic ionic liquid. The combined system catalyzes the hydrogenation of quinolines, pyridines, benzofurans, and furan to access the corresponding heterocycles, important molecules present in fine chemicals, agrochemicals, and pharmaceuticals. The catalyst is highly selective, acting only on the heteroaromatic ring, and not interfering with other reducible functional groups