A New Pentafluorothio-Substituted Curcuminoid with Superior Antitumor Activity.

Benedikt Linder,Rainer Schobert,Christel Herold-Mende,Lisa Reisbeck,Bernhard Biersack,Shrikant Anant,Leonhard H F Köhler,Donat Kögel,Dominic Menger,Dharmalingam Subramaniam

doi:10.3390/biom11070947

Abstract

A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid 1a was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound 1a was highly anti-proliferative and reached IC50 values in the nanomolar concentration range. 1a was superior to the known anti-tumorally active curcuminoid EF24 (2) and its known N-ethyl-piperidone analog 1b in all tested tumor cell lines. Furthermore, 1a induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. 1a also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that 1a strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.

Highlights

IntroductionCurcumin (compound 3) is a simple phenolic natural product isolated from the rhizome of the plant Curcuma longa
Curcumin is a simple phenolic natural product isolated from the rhizome of the plant Curcuma longa
We could previously demonstrate that Curcumin effectively targets GBM cells both in vitro and in vivo [46,47] and we could further show that this was mediated by inhibition of Signal Transducer and Activator of Transcription (STAT) 3, leading to reduced cell viability, induction of cell death and reduction of cell migration and invasion. here, we provide evidence that the novel compound 1a effectively reduces the viability of numerous cancer cell lines derived from multiple cancer entities

Summary

Introduction

Curcumin (compound 3) is a simple phenolic natural product isolated from the rhizome of the plant Curcuma longa. (compound 2) have shown improved anticancer activities when compared to curcumin as well as superior bioavailability, stability and uptake rates (Figure 1). The. SF and has shown distinct potential for the design of new anticancer active curcuminoids such chemically stable xenobiotic mimic of negatively charged biomolecules and it was labelled as 1b in an initial work of our group (Figure 1) [11,12]. The SF5 group is a chemically stable as “super trifluoromethyl group”, which is often superior more common fluoro and xenobiotic mimic of negatively charged biomolecules and it to was labelled as “super triflutrifluoromethyl substituents bioactive compounds [12]. Our fluoro working hypothesis is, that oromethyl group”, which is in often superior to more common and trifluoromethyl

Results

Discussion

Conclusion