Potent Cytotoxic Arylnaphthalene Lignan Lactones from Phyllanthus poilanei

Abstract

Two new (1 and 2) and four known arylnaphthalene lignan lactones (3–6) were isolated from different plant parts of Phyllanthus poilanei collected in Vietnam, with two further known analogues (7 and 8) being prepared from phyllanthusmin C (4). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (1) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds 1 and 7-O-[(2,3,4-tri-O-acetyl)-α-l-arabinopyranosyl)]diphyllin (7) found to be the most potent, exhibiting IC50 values of 170 and 110 nM, respectively. Compound 1 showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr nu/nu mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity.

Cytotoxic and natural killer cell stimulatory constituents of Phyllanthus songboiensis

“…In the current investigation, the highly cytotoxic arylnaphthalene lignan, (+)-acutissimalignan A ( 3 ), and etoposide were tested for their ability to induce topo IIα-mediated cleavage of plasmid DNA (Figure 4), using a method reported previously (Hasinoff et al, 2005). Consistent with previous reports (Hasinoff et al, 2012; Ren et al, 2014), the positive control etoposide (100 μM) exhibited topo IIα inhibitory activity, as assessed by cleavage of closed circular plasmid DNA to form linear double-stranded DNA, but the arylnaphthalene lignan lactone 3 did not show any topo II inhibition in this assay (Figure 4), indicating a different mechanism of action for 3 and etoposide.…”

“…The topo IIα-inhibitory activity of etoposide and compound 3 was assessed using a procedure reported previously (Hasinoff et al, 2005; Ren et al, 2014). In brief, assay buffer containing pBR322 DNA and test compound/DMSO were mixed and allowed to sit at room temperature for 30 min after which topo IIα was added to initiate the reaction.…”

“…Several diphyllin-type arylnaphthalene lignans have been characterized from this genus and found to exhibit potent cytotoxicity toward a number of human cancer cell lines (Ren et al, 2014; Tuchinda et al, 2006, 2008; Wu and Wu, 2006). Among these, phyllanthusmin D, a potently cytotoxic diphyllin diacetylated arabinoside isolated from P. poilanei , exhibited selective cytotoxicity against the HT-29 human colon cancer cells in vitro and antitumor potency in vivo when evaluated in an in vivo hollow fiber assay (Ren et al, 2014). This compound activated caspase-3 and induced apoptosis, but did not inhibit DNA topoisomerase IIα activity (Ren et al, 2014).…”

“…Among these, phyllanthusmin D, a potently cytotoxic diphyllin diacetylated arabinoside isolated from P. poilanei , exhibited selective cytotoxicity against the HT-29 human colon cancer cells in vitro and antitumor potency in vivo when evaluated in an in vivo hollow fiber assay (Ren et al, 2014). This compound activated caspase-3 and induced apoptosis, but did not inhibit DNA topoisomerase IIα activity (Ren et al, 2014). Also, several cytotoxic dichapetalin-type triterpenoids and aromatic diterpenoids have been reported from species in the genus Phyllanthus (Gunasekera et al, 1979; Qi et al, 2014; Sutthivaiyakit et al, 2003; Tuchinda et al, 2008).…”

Discovery of Anticancer Agents of Diverse Natural Origin

“…In the hollow-fiber assay, human cancer cells are propagated within fibers that are implanted either intraperitoneally or subcutaneously in immunodeficient mice, with the method being quite rapid and relatively sparing of the quantity needed of each compound evaluated (67, 70). Recent examples of compounds active in the in vivo hollow-fiber assay from our program project are the sesquiterpene lactone, goyazensolide (71) and the diphyllin glycoside, phyllanthusmin D (72). …”