Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells

Abstract

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.

Comparative Analyses of Bioactive Compounds in Inonotus obliquus Conks Growing on Alnus and Betula

“…Betulin and betulinic acid are obtained through the oxidation of pentacyclic triterpene, which has been shown to have antiproliferative, anti-inflammatory, and antineovascular activity. It has an effect on various types of cancer, in vitro and in vivo [ 32 ]. Betulin, betulinic acid, lupenone, and other pentacyclic triterpenes have been found to be cytotoxic in vitro against the human adenocarcinoma and melanoma models [ 33 ].…”

New Betulin Derivatives with Nitrogen Heterocyclic Moiety—Synthesis and Anticancer Activity In Vitro

“…Therefore, adding an indole group at the C-3 position of betulin allows to obtain derivatives with enhanced anticancer activity against estrogen-receptor-positive breast tumor cells. Previously, breast cancer cells have been shown to be sensitive to certain betulin derivatives, that contain a 1,2,3-triazole ring [ 41 ] or sulfonamide group [ 52 ].…”

Synthesis and Anticancer Activity of Indole-Functionalized Derivatives of Betulin

“…Thus, it can be concluded that the presence of the indole group at the C-28 position of the betulin skeleton increases the anticancer potential against the breast cancer cells. Similarly, Güttler et al [47] synthesized betulin sulfonamides and demonstrated their high antiproliferative and proapoptotic effects in breast cancer cells, suggesting that the betulin derivatives are promising compounds to treat aggressive breast tumors.…”

“…It is worth noting that betulin is easily isolated from plant material and the molecule can be modified to obtain more soluble derivatives [44]. In recent years, betulin has been used as a precursor for compounds with promising anticancer properties in vitro [17,[45][46][47]. Taking this into account, as well as the fact that the indole nucleus is a biologically accepted pharmacophore in many drugs, including anticancer agents, in this study, we synthesized new 28-indole-betulin derivatives.…”