The Phytochemistry of Selected Ancistrocladus and Monsonia Species and their Anti-Pancreatic Cancer and Nrf2 Activator Properties

Abstract

Fifteen naphthylisoquinoline (NIQ) alkaloids including four new compounds, the 5,8'-coupled ancistroyafungines A-C, and the 5,1'-linked ancistroyafungine D, as well as eleven known NIQs were isolated from the stem bark of an unidentified Ancistrocladus (Ancistrocladaceae) liana recently discovered in the North-Central region of the Democratic Republic of the Congo.

Most of the isolated alkaloids were S-configured at C-3, and possessed an oxygen function at C-6 in the isoquinoline portion, which is characteristic to the subclass of “Ancistrocladaceae-type” alkaloids. This finding was geo- and chemotaxonomically interesting since, except for one other Ancistrocladus species found in the Central Congo Basin, only Southeast Asian and East African Ancistrocladaceae are known to exclusively produce naphthylisoquinolines with these structural features. Moreover, the alkaloid pattern of this Congolese liana clearly differentiates this plant from all other Ancistrocladus taxa that have so far been botanically described, which suggests that it might represent a new species or subspecies. The new ancistroyafungines displayed strong preferential cytotoxic activities (with PC50 7.6 to 22.7 µM) towards human PANC-1 pancreatic cancer cells in nutrient-deprived medium, without showing toxicity in normal, nutrient-rich conditions.

Along with the above described naphthylisoquinoline alkaloids, nine other analytes including four flavonoids: quercetin, kaempferol, hyperoside, and isoquercetin, and five lignans: justicidins A and B, 6-methoxyjusticidin A, chinensinaphthol, and retrochinensinaphthol methyl ether were isolated from Monsonia angustifolia and Monsonia glauca plants collected in South Africa.

The extracts, the fractions, and compounds of M. angustifolia and M. glauca plants were screened for the first time for their Nrf2 activity. M. angustifolia sequential extracts exhibited superior Nrf2 activation with three active extracts, n-hexane, methanol, and aqueous extracts showing 169.0, 236.1, and 130.0% increase relative to the control. The methanol extract of M. angustifolia showed the strongest increase, better than that of sulforaphane (170.0%) used as positive control.

Seven fractions collected from the column chromatography of the methanol extract of M. angustifolia exhibited a good Nrf2 activation with percentage increase ranging from 106.0 to 199.0% relative to the control. The isolated flavonoids from these fractions were screened for Nrf2 activity but the tests were inconclusive as the compounds may have decomposed in DMSO during the lengthy storage process, nevertheless, these compounds have been previously reported to be Nrf2 modulators. Based on this, they are in all likelihood responsible of the good activity of the methanol extracts of both Monsonia species. This study was the first to report the presence of isolated flavonoids in M. angustifolia.

The isolated lignans were inactive against the human PANC-1 pancreatic cancer cell but they displayed strong to moderate activities against the HeLa cervical cancer cell. Justicidin B was the most potent compound of the isolated lignans with the IC50 value of 1.2 µM.

The UPLC-MS chromatograms of the two species showed them to be different, as justicidin B was mainly found in M. glauca while justicidin A and 6-methoxyjusticidin A were predominant in M. angustifolia. To the best of our knowledge, this is the first report on the presence of justicidin B in Monsonia glauca, as well as its phytochemical properties and its bioactivities.