Curcumin and Its New Derivatives: Correlation between Cytotoxicity against Breast Cancer Cell Lines, Degradation of PTP1B Phosphatase and ROS Generation.

Tomasz Kostrzewa,Karol Wołosewicz,Marcin Kołaczkowski,Joanna Drzeżdżon,Julia Siemińska,Dagmara Jacewicz,Magdalena Górska-Ponikowska,Ryszard Łaźny,Marek Jamrozik,Alicja Kuban-Jankowska

doi:10.3390/ijms221910368

Abstract

Breast cancer is the most common cancer of women—it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.

Highlights

The prevalence of various types of cancer leads scientists to look for new active substances that can serve as medicines
Lithium enolates generated in the reaction of the ketones with LDA were acylated with acyl cyanides affording compounds 4, 6, 8, and 12 or compound 3
Compound 11 was obtained with a lower yield (35%) due to difficulty in purification of the product— chromatography repeated several times resulted in an impure product, which had to be purified by recrystallization with dichloromethane (DCM)

Summary

Introduction

The prevalence of various types of cancer leads scientists to look for new active substances that can serve as medicines. Among the various groups of potential drug candidates, low molecular weight organic compounds are a major group and many of them are derived from biomolecules of natural origin. One of the prospective substances, due to a wide range of activity in vivo tests and low toxicity, is curcumin [(1,7-bis(4-hydroxy-3methoxyphenyl)-1,6-heptadiene-3,5-dione)] (Figure 1) [1,2]. Many of them are derived from biomolecules of natural substances, due to a wide range of activity in vivo tests an bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-23of,252 -dion. FigTuhirseph1e.noSlitcrcuomctpuournedoisfaccuonrsctituumentionf t(hke enattournaleintgareudtieonmt ofetrh)e.rhizome of Curcuma longa and is widely used in traditional eastern medicine.

Methods

Results

Discussion

Conclusion