Antiproliferative Constituents of the Roots of Ethiopian Podocarpus falcatus and Structure Revision of 2α-Hydroxynagilactone F and Nagilactone I

Abstract

Bioassay-guided fractionation using the human colorectal adenocarcinoma (HT-29) cell line of the methanol extract of dried roots of Podocarpus falcatus led to the isolation of two new type C nagilactones, 16-hydroxynagilactone F (1) and 2β,16-dihydroxynagilactone F (2), and the new totarane-type bisditerpenoid 7β-hydroxymacrophyllic acid (4), along with the seven known compounds 2β-hydroxynagilactone F (3), macrophyllic acid (5), nagilactone D (6), 15-hydroxynagilactone D (7), nagilactone I (8), inumakiol D (9), and ponasterone A (10). The structures of the new compounds were determined by 1D and 2D NMR, HRESIMS, UV, and IR and by comparison with the reported spectroscopic data of their congeners. The orientation of the C-2 hydroxy group of 3 and 8 was revised to be β based on evidence from detailed analysis of 1D and 2D NMR data and single-crystal X-ray diffraction studies. Among the isolated compounds, the nagilactones, including the new dilactones 16-hydroxynagilactone F (1) and 2β,16-dihydroxynagilactone F (2), were the most active (IC50 0.3-5.1 μM range) against the HT-29 cell line, whereas the bisditerpenoids (4 and 5) and the other known compounds 9 and 10 were inactive. The presence of the bioactive nagilactones in P. falcatus supports its traditional use.

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer, Part 2: A Review on Cytotoxic, Antiproliferative, and Antitumor Phytochemicals, and Future Perspective

“…Among the different types of triterpenoids, pentacyclic triterpnoids display the most potent anti-inflammatory and anticancer activity [ 62 ]. Addo et al [ 63 ] reported the isolation of two new nagilactones along with seven known from the root of Podocarpus falcatus (Thunb.) collected from Berga forest, Addis Alem, central Ethiopia.…”

Two New Anti‐Proliferative C18‐Norditerpenes from the Roots of Podocarpus macrophyllus

“…Therefore, the structure of 2 was defined as 3b-hydroxymakilactone A ( Figure 1). Compounds 4 -12 ( Figure 1) were identified as inumakilactone B (4), [9] 2b-hydroxynagilactone F (5), [15] nagilactone F (6), [13] 2,3-dehydronagilactone F (7), [16] nagilactone G (8), [9] inumakilactone A (9), [17] makilactone M (10), [18] nagilactone C (11), [18] and l-deoxy-2-hydroxynagilactone A (12) [12] by comparing their observed NMR data with reported data. The 1D-NMR spectroscopic data of 3 (Tables 1 and 2) were coincident with reported data of 2,3-dihydro-2αhydroxypodolide, which has been identified from Ileostylus micranthus, [14] indicating that they were the same compound.…”

“…Furthermore, the X-ray diffraction experiment (flack parameter = 0.06 (3) Thus, the structure of 3 should be revised as 2,3-dihydro-2b-hydroxypodolid ( Figure 1). Compounds 4 -12 ( Figure 1) were identified as inumakilactone B (4), [9] 2b-hydroxynagilactone F (5), [15] nagilactone F (6), [13] 2,3-dehydronagilactone F (7), [16] nagilactone G (8), [9] inumakilactone A (9), [17] makilactone M (10), [18] nagilactone C (11), [18] and l-deoxy-2-hydroxynagilactone A (12) [12] by comparing their observed NMR data with reported data.…”

Bioactivity-Guided Isolation of Totarane-Derived Diterpenes from Podocarpus neriifolius and Structure Revision of 3-Deoxy-2α-hydroxynagilactone E

“…A subsequent literature search for this chemical structure revealed that the collected 1 H and 13 C NMR data for 1 matched with those of 3-deoxy-2 α -hydroxynagilactone E ( 8 ), previously isolated from Podocarpus nagi [20]. However, careful inspection of the 1 H NMR data measured in methanol- d 4 revealed that the splitting pattern and coupling constants ( J) values of H-2 (dddd, J  = 13.5, 8.5, 7.4, 4.9 Hz) shared a close similarity with those of the revised C-type podolactone 2 β -hydroxynagilactone F (H-2, dddd, J  = 12.9, 9.1, 7.2, 5.1 Hz) [21], and suggested a comparable 2 β configuration of the hydroxy group substitution at C-2. A very recent study on P. nagi reporting the X-ray structure of 3-deoxy-2 β -hydroxynagilactone E confirmed this assertion [11].…”