Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans

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.

Constituents of Bupleurum praealtum and Bupleurum veronense with Potential Immunomodulatory Activity

“…Interestingly, when Mφs were exposed to the two highest concentrations of arcitin (100 and 10 μM, Figure S10, Supporting Information), the opposite effect to the one on SPCs was found, i.e., a statistically significant increase in Mφ ability to accumulate NR (Figure S10, Supporting Information). Arcitin was previously found to exhibit marked cytotoxicity toward Jurkat T cells (immortalized human T lymphocytes) and to lower the amount of IgE in cultures of U266 cells in a concentration-dependent manner (immortalized human B lymphocytes) . The present results with primary cell cultures of rat spleen lymphocytes (and macrophages) showed that (+)-arcitin does not reduce their viability but stimulates their ability to both metabolize MTT and accumulate NR, suggesting a functional potentiation of these immune cells.…”

“…Two related dibenzylbutyrolactones were additionally isolated from B. praealtum extracts, one of which is a known compound, from the B. praealtum aerial parts’ extract, straightforwardly identified as (+)-arcitin ( syn. O , O -dimethylmatairesinol, Figure S6.5, Supporting Information), by comparison of its NMR data with the previously reported ones . The NMR, MS, and IR spectra of the other lignan ( 6 , Figure ), isolated from the B. praealtum schizocarp extract, pointed to an oxygenated derivative of arcitin, possessing a keto function in position 7.…”

“…Compound 5 (23 mg) was isolated from the B. praealtum aerial parts’ extract in the first silica gel dry-flash chromatography, located in fraction 25 which was eluted with hexane-Et 2 O (1:3, v/v). Fraction 30 (EtOAc–MeOH, 7:3, v/v), 12 mg, represented pure (+)-arcitin (synonym dimethylmatairesinol) . Additionally, the initial chromatography of the B. praealtum aerial parts’ extract resulted in fractions 11 and 12, 5, and 10 mg, respectively, both eluted with 15% (v/v) Et 2 O in hexane, that contained, based on GC–MS analyses, compound 2 , unfortunately in a complex mixture.…”

Stereoselective Total Synthesis of (+)-Aristolactam GI

“…Due to its unique structural arrangement, having features of both an aristolactam and a 1,4-benzodioxane neolignan, it was of great interest to synthesize this unusual natural product. While our group has previously synthesized a number of lignan natural products, − including 1,4-benzodioxane neolignans, − our methodology has not been extended to such a complex 1,4-benzodioxane such as (+)-aristolactam GI ( 1 ).…”

Lignans

“…Davidson et al have presented their work on their novel, efficient, convergent, and modular synthesis of the well-known dibenzyl butyrolactone lignans through the use of the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate [7]. Not only were the natural products able to be obtained, but the reported synthetic route also enabled the modification of these lignans to give rise to 5-hydroxymethyl derivatives, which were then shown to have 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.…”