Synthesis of Usnic Acid Derivatives and Evaluation of Their Antiproliferative Activity against Cancer Cells

Abstract

Usnic acid is a secondary metabolite abundantly found in lichens, for which promising cytotoxic and antitumor potential has been shown. However, knowledge concerning activities of its derivatives is limited. Herein, a series of usnic acid derivatives were synthesized and their antiproliferative potency against cancer cells of different origin was assessed. Some of the synthesized compounds were more active than usnic acid. Compounds 2a and 2b inhibited survival of all tested cancer cell lines in a dose- and time-dependent manner. Their IC50 values after 48 h of treatment were ca. 3 μM for MCF-7 and PC-3 cells and 1 μM for HeLa cells, while 3a and 3b revealed antiproliferative activity only against HeLa cells. All active usnic acid derivatives induced G0/G1 arrest and a drop in the fraction of HeLa cells in the S and G2/M phases. Compounds 2a and 2b decreased the clonogenic potential of the cancer cells evaluated and induced cell cycle arrest at the G0/G1 phase and apoptosis in MCF-7 cells. Moreover, they induced massive cytoplasmic vacuolization, which was associated with elevated dynein-dependent endocytosis, a process that has not been reported for usnic acid and indicates a novel mechanism of action of its synthetic derivatives. This work also shows that naturally occurring usnic acids are promising lead compounds for the synthesis of derivatives with more favorable properties against cancer cells.

Anticancer Potential of Lichens’ Secondary Metabolites

“…Derivatives 2a and 2b also activated strong cytoplasmic vacuolization, which was associated with dynein-dependent endocytosis. This mechanism has not yet been demonstrated in UA and it is the first time reported in synthetic derivatives of UA [72]. The potasium usnate (PU), which was prepared to enhance the solubility of UA, demonstrated cytotoxic activity in each tested colorectal cancer cells (human HCT116, DLD1, SW480, HT29, SW620, Caco2, COLO320, and mouse CT26) with lower IC50 values than UA except of SW480 and CT26 cells.…”

Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

“…Recently, isoxazole and pyrazole derivatives of (+)-UA and racemic UA were synthesised [51]. The authors hypothesised that replacement of the 1,3-dicarbonyl functionality by bioisosteric heterocycles would lock the accessible conformation of UA into more rigid and defined arrangements, which would decrease pleiotropic effects derived from rotational freedom and equilibria of stereoisomers.…”

“…Normal human skin fibroblasts appeared to be more resistant to these compounds (IC 50 = 9.2 μM). Mechanism of their activity relied on the G0/G1 cell cycle arrest and induction of apoptosis with concomitant massive cytoplasmic vacuolisation (Table 1) [51].…”

The expression profiles of apoptosis-related genes induced usnic acid in SK-BR-3 breast cancer cell

“…7,9 Its chemical property can be described as 2,6-diacetyl-7,9-dihydroxy-8,9bdimethyldibenzofuran-1,3(2H,9bH)-dione. 10 The ability to easily isolate high purity UA from different types of lichen species makes UA an important drug candidate molecule. Especially in recent studies, UA shows antiproliferative effects on different cancer cell lines.…”

“…Especially in recent studies, UA shows antiproliferative effects on different cancer cell lines. [10][11][12] It has been reported that UA shows antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cells in recent studies. 13,14 Eskiler et al investigated the effects of UA and tamoxifen or enzalutamide on MCF-7 breast cancer cells and LNCaP prostate cancer cells.…”