Synthesis of Xanthohumol Analogues and Discovery of Potent Thioredoxin Reductase Inhibitor as Potential Anticancer Agent

Abstract

The selenoprotein thioredoxin reductases (TrxRs) are attractive targets for anticancer drugs development. Xanthohumol (Xn), a naturally occurring polyphenol chalcone from hops, has received increasing attention because of its multiple pharmacological activities. We synthesized Xn and its 43 analogues and discovered that compound 13n displayed the highest cytotoxicity toward HeLa cells (IC50 = 1.4 μM). Structure-activity relationship study indicates that the prenyl group is not necessary for cytotoxicity, and introducing electron-withdrawing group, especially on the meta-position, is favored. In addition, methylation of the phenoxyl groups generally improves the potency. Mechanistic study revealed that 13n selectively inhibits TrxR and induces reactive oxygen species and apoptosis in HeLa cells. Cells overexpressing TrxR are resistant to 13n insult, while knockdown of TrxR sensitizes cells to 13n treatment, highlighting the physiological significance of targeting TrxR by 13n. The clarification of the structural determinants for the potency would guide the design of novel potent molecules for future development.

Polyphenols as mitochondria-targeted anticancer drugs

“…A derivative of xanthohumol, a prenylated chalconoid found in hops (Humulus lupulus), induced oxidative stress and apoptosis in human cervical cancer HeLa cells with IC50 of 1.4 μM [36]. The derivative proved to act as TRX-R inhibitor; overexpression of the enzyme and its knockdown rendered the cells more resistant or more sensitive, respectively, to the proapoptotic activity of the derivative.…”

Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents

“…However, the high cytotoxicity of PL hinders its application as a cytoprotective agent. 21 As our continued interests in discovering and developing novel redox active small molecules as potential therapeutic or diagnostic agents, 30,32,34,[44][45][46][47] we described the synthesis of PL and its analogues, and the discovery of two potent compounds (4 and 5) as potential neuroprotective agents to rescue the H 2 O 2 -or 6-OHDA-induced PC12 cell damage. Compared to the cytotoxicity data of 4 (a compound lacking the M2 moiety), PL shows greater toxic to both L02 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 cells and PC12 cells.…”

“…The same amounts of DMSO were added to the control experiments and the activity was expressed as the percentage of the control.Trx and TrxR activity assays. Measuring cellular Trx and TrxR activity were performed by following our published protocols 30,. 31, 63 Briefly, the cell extract containing 20 µg of total proteins was incubated in a final reaction volume of 50 µL 100 mM Tris-HCl (pH 7.4) containing 0.3 mM insulin, 660 µM NADPH, 3 mM EDTA and 60 nM recombinant rat TrxR1 (for assaying the Trx activity) or 4 µM E. coli Trx (for assaying the TrxR activity) for 30 min at 37 °C.…”

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

“…Supported by these observations, the thioredoxin system has been emerging as an important target for cancer treatment. Consequently, various small molecules targeting the thioredoxin system have been discovered and developed as potential cancer chemotherapeutic agents in past years (13)(14)(15)(16)(17)(18)(19)(20).…”