Abstract
Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.
Highlights
Dibenzyl butyrolactone lignans 1 are a class of lignans which have been reported to exhibit a range of biological activities, including, but not limited to neuroprotective [1], anti-cancer [2,3], anti-inflammatory [2,4], and anti-aging effects [5]
Extensive work has gone into the study of these compounds and their related analogues to explore and establish structure–activity relationships and the possible use of these lignans as lead compounds for therapeutics
Whilst previous work has explored the synthesis of these lignans and analogues thereof [14,15,16], mainly focusing on changing the substituents on the aryl rings [17], one area that has not been extensively investigated is the synthesis of C-5 substituted analogues of these butyrolactone lignans, represented by 4
Summary
Dibenzyl butyrolactone lignans 1 are a class of lignans which have been reported to exhibit a range of biological activities, including, but not limited to neuroprotective [1], anti-cancer [2,3], anti-inflammatory [2,4], and anti-aging effects (see Figure 1) [5]. Perhaps the most notable of these biological properties is their reported potent anti-proliferative activities; examples of this class include (−)-matairesinol 2 and (−)-arctigenin 3 which, along with their synthesized derivatives, have been shown to exhibit excellent activity against various cancer cell lines, including pancreatic, breast, endometrial, colorectal, lung, and bladder cancers [6,7,8,9,10,11,12] Owing to their anti-cancer properties and their classification as drug-like compounds [13]. Whilst previous work has explored the synthesis of these lignans and analogues thereof [14,15,16], mainly focusing on changing the substituents on the aryl rings [17], one area that has not been extensively investigated is the synthesis of C-5 substituted analogues of these butyrolactone lignans, represented by 4.
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