A Dihydrobenzofuran Lignan Induces Cell Death by Modulating Mitochondrial Pathway and G2/M Cell Cycle Arrest

Abstract

A dihydrobenzofuran lignan, the dimerization product of caffeic acid methyl ester, has shown pronounced antileishmanial and antiplasmodial activities. The present study showed the effect of this compound on cell cycle and apoptosis. Flow cytometric analysis revealed that the cells were arrested in the G2/M phase. Activation of caspase 3, but not caspase 8, generation of ROS, upstream of caspase-3, release of cytochrome c,increase in Bax level, and decrease in Bcl-2 level suggested the involvement of mitochondrial damage. Loss of mitochondrial transmembrane potential independent of caspase activation further suggested the mode of apoptosis. Dihydrobenzofuran-mediated cell death was absent in Bcl-xL-overexpressed cells. Overall, our results justify the role of dihydrobenzofuran lignan as potential antitumor agent, causing G2/M arrest and apoptosis involving the mitochondrial controlled pathway. These findings open promising insights as to how this specific dihydrobenzofuran lignan mediates cytotoxicity and may prove a molecular rationale for future therapeutic interventions in carcinogenesis.

Biomimetic Synthesis of Natural and “Unnatural” Lignans by Oxidative Coupling of Caffeic Esters

“…Of these, 3 has been very recently reported as a promising cell death inducer by modulating the mitochondrial pathway and G2/ M cell cycle arrest. [4] The benzoxanthenes 6 and 15 are related to compounds reported as potential antitumour agents. [32] In addition, the benzoxanthene lignans are strongly fluorescent both in solution and in the solid state under UV light at 366 nm (Figure 6), and this property may be of considerable interest in the design of new fluorescent probes for biomedical applications.…”

“…According to IUPAC recommendations, [2] "neolignans" are dimers that originate from coupling other than 8-8Ј coupling, although the term "lignan" is frequently employed in a broader sense (including neolignan), as in the title of this article. Lignans, neolignans and other related compounds are accumulated in vascular plants as a chemical defence system, [3] and this may explain their diverse biological activities, including cytotoxic, [4] antimitotic, antileishmanial, [5] antiangiogenic, [6] cardiovascular [7] and antiviral activity. [8] The biological activities and structural variety of lignans and related compounds make them an attractive target for chemical synthesis or modification.…”

Synthesis of dihydrobenzofurans and dihydroindoles by intramolecular Friedel-Crafts reaction of aryloxy- and arylamino-substituted propargylic alcohols

“…1,2 Although several general methods for their synthesis have been developed, [3][4][5][6][7][8][9][10][11][12] they often suffer from the use of expensive transition-metal catalysts or toxic reagents and multistep preparation of the starting materials. Hence, efficient and general methods for the synthesis of both dihydrobenzofurans and dihydroindoles from easily accessible starting materials using inexpensive and low-toxicity catalysts are still needed.…”

Biomimetic Synthesis of Lignans

“…This chapter will focus on the biomimetic synthesis of lignans. In Nature, lignan chemotypes 4-14 are produced as either racemates (though usually a single diastereomer) or, in some cases, as single enantiomers [3][4][5][6][7][8][9][10][11][12][13][14]. In Scheme 18.2 One-electron oxidation of (E)-coniferyl alcohol (19) to multiple quinone methide mesomeric radicals 21-23, which combine to give rise to neolignans (coupling products other than .…”

“…This lack of stereocontrol is observed with both metal-catalyzed (Ag I , Mn II , I III , Cu II , Co II , Fe II ) oxidative phenolic couplings as well as enzyme-mediated [horse radish peroxidase (HRP), laccases, oxidases] oxidative phenolic couplings [3][4][5][6][7][8][9][10][11][12][13][14]. In Nature, the stereochemical outcome of these radical couplings is somehow controlled to provide enantiopure lignans.…”