Isolation of Bioactive Rotenoids and Isoflavonoids from the Fruits of Millettia caerulea

Abstract

Three new rotenoids (1–3), two new isoflavonoids (4 and 5), and six known analogues (6–11) were isolated from a n-hexane partition of a methanol extract of the fruits of Millettia caerulea, with the structures of the new compounds elucidated by analysis of their spectroscopic data. The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data, and their absolute configurations were established using ECD spectra and specific rotation values. All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line, and the known compounds, (−)-3-hydroxyrotenone (6) and (−)-rotenone (7), were found to be potently active. When tested in a NF-κB inhibition assay, compound 6 showed activity. This compound, along with the new compound, (−)-caeruleanone D (1), and the known compound, ichthynone (8), exhibited K-Ras inhibitory potency. Further bioactivity studies showed that the new compounds, (−)-3-deoxycaeruleanone D (2) and (−)-3-hydroxycaeruleanone A (3), and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells.

An Intramolecular CAr–H•••O=C Hydrogen Bond and the Configuration of Rotenoids

“…1). In turn, most of these sub-groups of rotenoids can be divided further into two groups, “rotenone-like” rotenoids, containing a C-7 furan-fused 2-methyl-3- O -1-buten-4-yl unit, and “deguelin-like” rotenoids, incorporating a C-7 pyran-fused 3-methyl-3- O -1-buten-1-yl unit, respectively [19] (Fig. S1, Supporting Information).…”

“…The antitumor propensity of rotenoids, which was reported to correlate with their Complex I inhibitory effects, has attracted an increasing interest [13–15]. In our previous work, (−)-rotenone and its analogues and (−)-tephrosin were found to exhibit cytotoxicity toward a small panel of human cancer cell lines [16–19], with similar effects observed for deguelin and 13-homo-13-oxa-2,3-dehydrodeguelin by other groups [20, 21]. Interestingly, deguelin was found to show in vivo cancer chemopreventive and antitumor effects [22, 23].…”

“…The structure of the parent compound, rotenone, has been ascertained by investigation of its NMR spectroscopic data [25, 26] and confirmed by X-ray crystallography [27], with its (2 S , 3 S , 2″ R ) absolute configuration established by a series of chemical reactions [28] and confirmed by single-crystal X-ray diffraction analysis for 5'-bromorotenone [29]. The electronic circular dichroism (ECD) spectra of rotenone and several analogues have been investigated, with the Cotton effects (CEs) characterized [19, 30]. Although the CEs above 300 nm were not suggested as reliable configurational assignments for some 3-substituted rotenoids [31], it has been well documented that these CEs are suitable for indicating the absolute configuration at C-2 and C-3 of 3-hydroxyrotenoids [19, 32].…”

“…The electronic circular dichroism (ECD) spectra of rotenone and several analogues have been investigated, with the Cotton effects (CEs) characterized [19, 30]. Although the CEs above 300 nm were not suggested as reliable configurational assignments for some 3-substituted rotenoids [31], it has been well documented that these CEs are suitable for indicating the absolute configuration at C-2 and C-3 of 3-hydroxyrotenoids [19, 32]. …”

Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents

“…HT-29 was the only human tumor cell line on hand that displayed high selectivity for the most cytotoxic extracts through its low susceptibility, with unpublished, internal project data suggesting that a signature of only ~5% (or less) of sample extracts evaluated bore significant activity against HT-29 cells. In terms of the P01 project itself, the consequent focus on HT-29 cells and human colon adenocarcinoma by association has led to screening for inhibitory activity in the K-ras pathway, becoming one of the major mechanistic assays emphasized (Peruchot et al, 1987;Ren et al, 2014). HT-29 cells are also significant in that the cell line has long been and continues to be included in the NCI-60 panel utilized for the COMPARE algorithm to predict mechanism of action for cytotoxic compounds (Paull et al, 1989;Shoemaker, 2006).…”