The Influence of Betulin and Its Derivatives EB5 and ECH147 on the Antioxidant Status of Human Renal Proximal Tubule Epithelial Cells.

Celina Kruszniewska-Rajs,Elwira Chrobak,Agnieszka Synowiec-Wojtarowicz,Stanisław Boryczka,Magdalena Kimsa-Dudek,Ewa Bębenek,Joanna Magdalena Gola,Barbara Strzałka-Mrozik,Stanisław Głuszek

doi:10.3390/ijms23052524

Abstract

Betulin and its derivatives, 28-propyne derivative EB5 and 29-diethyl phosphonate analog ECH147, are promising compounds in anti-tumor activity studies. However, their effect on kidney cells has not yet been studied. The study aimed to determine whether betulin and its derivatives—EB5 and ECH147—influence the viability and oxidative status of human renal proximal tubule epithelial cells (RPTECs). The total antioxidant capacity of cells (TEAC), lipid peroxidation product malondialdehyde (MDA) level, and activity of antioxidant enzymes (SOD, CAT, and GPX) were evaluated. Additionally, the mRNA level of genes encoding antioxidant enzymes was assessed. Cisplatin and 5-fluorouracil were used as reference substances. Betulin and its derivatives affected the viability and antioxidant systems of RPTECs. Betulin strongly reduced TEAC in a concentration-dependent manner. All tested compounds caused an increase in MDA levels. The activity of SOD, CAT, and GPX, and the mRNA profiles of genes encoding antioxidant enzymes depended on the tested compound and its concentration. Betulin showed an cisplatin-like effect, indicating its nephrotoxic potential. Betulin derivatives EB5 and ECH147 showed different impacts on the antioxidant system, which gives hope that these compounds will not cause severe consequences for the kidneys in vivo.

Highlights

The reduction in cell viability below 70% proves the cytotoxic effect of the compound was
For renal proximal tubule epithelial cells, the mildest compound inwas a decrease in cell viability below
We have previously reported that the mRNA levels of GAPDH and βactin genes changed in renal proximal tubule epithelial cells (RPTECs) depending on AmB modification treatment [39]

Summary

Introduction

The attachment of compounds containing a fragment with a carbon–carbon triple bond seems to be promising in the context of antitumor activity This allows for the potential enhancement of the anticancer effect and allows for further chemical modifications of the derivatives obtained in this way [4]. Many active substances registered as drugs (e.g., ethinyloestradiol, levonorgestrel, selegiline, pargyline, rasagiline, pralatrexate, erlotinib, ponatinib, terbinafine, tazarotene) have internal or terminal alkynyl groups [5] This is because a triple bond, due to its unique properties, can perform many different functions, directly or indirectly influencing the biological activity of chemical compounds. The phosphonate group containing a direct bond between the carbon and phosphorus atom is isosteric to the phosphate group commonly found in living organisms The introduction of this group into the molecules of biologically active substances can lead to a significant improvement in their therapeutic properties

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