Synthesis, Biological Evaluation of Fluorescent 23-Hydroxybetulinic Acid Probes, and Their Cellular Localization Studies

Abstract

23-Hydroxybetulinic acid (23-HBA) is a complex lupane triterpenoid, which has attracted increasing attention as an anticancer agent. However, its detailed mechanism of anticancer action remains elusive so far. To reveal its anticancer mode of action, a series of fluorescent 23-HBA derivatives conjugated with coumarin dyes were designed, synthesized, and evaluated for their antiproliferative activities. Subcellular localization and uptake profile studies of representative fluorescent 23-HBA probe 26c were performed in B16F10 cells, and the results suggested that probe 26c was rapidly taken up into B10F10 cells in a dose-dependent manner and mitochondrion was the main site of its accumulation. Further mode of action studies implied that the mitochondrial pathway was involved in 23-HBA-mediated apoptosis. Together, our results provided new clues for revealing the molecular mechanism of natural product 23-HBA for its further development into an antitumor agent.

Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives

“…To date, there have been few studies on 23‐hydroxybetulinic acid ( 14 ), although the majority of the existing works associate this triterpene to antitumor activity, with reported action against melanoma [51] and breast cancer cell lines [52] . Additionally, 23‐hydroxybetulinic acid presents cytotoxicity through mitochondrial pathway apoptosis, autophagy and cell cycle arrest in HL‐60, a human acute promyelocytic leukemia cell line [53] .…”

Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents

“…Besides, HBA induced apoptosis of human leukemia HL-60 cells by inhibiting the expression of Bcl-2 and telomerase activity [8]. The results of subcellular localization and uptake profile studies of fluorescent HBA probe suggested that mitochondrion was the main site of probe accumulation in B16F10 cells [9]. The mitochondrion-targeted apoptosis in cancer cells along with the low toxicity in normal cells have made HBA derivatives as new promising chemotherapeutic candidates for the intervention of cancers.…”

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

“…HBA 4 was also used to perform esterification reactions [18,50,51]. Zhang et al prepared C-28 ester derivatives of HBA bearing different substituents 79 by the treatment of 3-oxo-HBA 78a with appropriate halides under basic conditions (Scheme 13) [18].…”

“…Another interesting report involving esterification reactions at 23-OH group of HBA 4 was published by Yao et al [51]. The authors synthesized a series of fluorescent HBA derivatives conjugated with coumarin dyes 82 and evaluated them for their antiproliferative activity.…”