Bioactive ent-kaurane diterpenoids from Isodon rubescens.

Seven previously undescribed 7,20-epoxy-ent-kaurane diterpenoids, isojiangrubesins A-G, along with seventeen known ones, were isolated from the aerial parts of Isodon rubescens. Their structures were characterized on the basis of spectroscopic methods and signal-crystal X-ray diffraction. All of these compounds were evaluated for their in vitro cytotoxicity against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). Four isolates exhibited significant inhibitory ability against all cell lines, with IC50 values ranging from 0.5 to 6.5 µM; They also strongly inhibited NO production in LPS-stimulated RAW264.7 cells.

Diterpenoids from Isodon species: an update.

Covering: December 2005 to June 2016. Previous review: Nat. Prod. Rep., 2006, 23, 673-698Over the last decade, great efforts have been made to conduct phytochemistry research on the genus Isodon, which have led to the isolation and identification of a number of diterpenoids. At the same time, these newly reported diterpenoids with diverse structures have led to new findings on their biological functions and chemical synthesis research. In this update, we review more than 600 new diterpenoids, including their structures, classifications, biogenetic pathways, bioactivities, and chemical synthesis.

Structurally Diverse Diterpenoids from Isodon scoparius and Their Bioactivity.

Fourteen new diterpenoids (1-14) based on four skeletal types and two known analogues (15 and 16) were isolated from the aerial parts of Isodon scoparius. Compound 2 is the first ent-kaurane diterpenoid featuring a 1,11-ether bridge, and the structures of these new compounds were established mainly by NMR and MS methods. The absolute configurations of 1 and 5 and the relative configuration of 3 were determined using single-crystal X-ray diffraction. The absolute configuration of 14 was determined by comparison of the experimental and calculated electronic circular dichroism spectra. Compounds 1, 4, and 15 were active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and they also inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values of 1.0, 3.1, and 1.8 µM, respectively.

Dibenzocyclooctadiene lignans from Kadsura heteroclita.

Sixteen dibenzocyclooctadiene lignans, including eight new ones, kadheterins A-H (1-8), and a new natural product, 9-benzoyloxy-gomisin B (9), were isolated from the stems of K. heteroclita. The structures of 1-9 were elucidated by extensive spectroscopic methods, and their absolute configurations were determined by combining CD with ROESY experiments. Additionally, the absolute configuration of 1 was further confirmed by single crystal X-ray crystallographic analysis. In vitro activity assays showed that 1 exhibited moderate cytotoxicity against HL-60 with IC50 value at 14.59µM.

Two New Compounds from Schisandra propinqua var. propinqua.

Schisanpropinoic acid (1), a new bergamotane sesquiterpenoid, and schisanpropinin (2), a new tetrahydrofuran lignan with a rare epoxyethane unit, were identified from the stems and leaves of Schisandra propinqua var. propinqua. Their structures were determined based on comprehensive spectroscopic and mass spectrometric analysis. The absolute configuration of 1 was determined by X-ray analysis. Compounds 1 and 2 were tested for their cytotoxic activity against five human tumor cell lines.

Longikaurin A, a natural ent-kaurane, suppresses stemness in nasopharyngeal carcinoma cells.

Cancer stem cells (CSCs) are a small proportion of tumor cells that may be responsible for tumor metastasis and recurrence. Our recent research indicated that longikaurin A (LK-A) exhibited anti-tumor activity in nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Here, we further investigated whether LK-A could suppress the stemness of NPC cells. Sphere formation assay was used to assess the self-renewal ability of the cells treated with LK-A. Side population (SP) was determined by flow cytometry to measure the influence of LK-A on NPC SPs. The expression of the c-myc and fibronectin was detected by western blotting. The cytotoxicity of LK-A in combination with cisplatin to NPC cells was determined by MTT assay. Colony formation assay was used to verify whether LK-A could sensitize NPC cells to radiation and reverse the radiotherapy resistance. In the present study, we found that LK-A reduced the number and size of spheroid formation and decreased the SP cell percentage of the S18 cell line at a low concentration. Furthermore, LK-A treatment downregulated the expression of c-myc and fibronectin in NPC cell lines. Moreover, LK-A could significantly enhance the chemotherapeutic and radiotherapeutic sensitivity of NPC cell lines and reverse acquired radiotherapy resistance of Sune2-IR. Our data revealed that LK-A could suppress the stemness of NPC cells and may enhance the efficacy of radiotherapy and chemotherapy.

Ent-Abietanoids Isolated from Isodon serra.

Four new ent-abietane diterpenoids, along with four known ones were isolated from the aerial parts of Isodon serra, a traditional Chinese folk medicine. The new diterpenoids were named as serrin K (1), xerophilusin XVII (2), and enanderianins Q and R (3 and 4), while the known ones were identified as rubescansin J (5), (3α,14ß)-3,18-[(1-methylethane-1,1-diyl)dioxy]-ent-abieta-7,15(17)-diene-14,16-diol (6), xerophilusin XIV (7), and enanderianin P (8), respectively. Their structures were elucidated by extensive spectroscopic analysis and comparison with the literature. Compound 1 showed remarkable inhibitory activity towards NO production in LPS-stimulated RAW264.7 cells (IC50 = 1.8 µM) and weak cytotoxicity towards five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480).

Rearranged 6/6/5/6-Fused Triterpenoid Acids from the Stems of Kadsura coccinea.

Fourteen new rearranged 6/6/5/6-fused triterpenoid acids, namely, kadcoccine acids A-N (1-14), were isolated from an EtOAc-soluble extract of the stems of Kadsura coccinea. Their structures were characterized mainly by analyzing 1D and 2D NMR and HRESIMS data and were shown to feature a rare 14(13→12)-abeo-lanostane skeleton. Compounds 7 and 8 represented the first examples of a 5-substituted 2(5H)-furanone motif on the C-17 side chain of this skeleton. The absolute configurations of C-23 for compounds 1, 7, and 8 were determined by comparison of their experimental electronic circular dichroism spectra. All the isolates were screened for their in vitro cytotoxicity against six human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW-480, and HeLa), and compounds 2 and 8 exhibited weak inhibitory effects with IC50 values ranging from 3.11 to 7.77 µM.

Bioactive ent-kaurane diterpenoids from Isodon serra.

Nine 7,20-epoxy-ent-kaurane diterpenoids (15-acetylmegathyrin B, serrin E, 14ß-hydroxyrabdocoestin A, serrin F, serrin G, 11-epi-rabdocoestin A, serrin H, serrin I, and 15-acetylenanderianin N), along with seven known ones, were isolated from the aerial parts of Isodon serra. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configuration of 15-acetylmegathyrin B was determined by signal-crystal X-ray diffraction. All of these compounds were evaluated for their cytotoxic activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480). Serrin F, rabdocoestin B and 1α,11ß-dihydroxy-1α,11ß-acetonide-7α,20-epoxy-ent-kaur-16-en-15-one showed cytotoxic activities against all cell lines, with IC50 values ranging from 0.7 to 4.6 µM; serrin F also strongly inhibited NO production in LPS-stimulated RAW264.7 cells. Otherwise, 14ß-hydroxyrabdocoestin A, serrins H and I, as well as enanderianin N and megathyrin B, also exhibited inhibitory effects towards NO production, while no cytotoxicity against five cell lines was detected.

Phomopchalasins A and B, Two Cytochalasans with Polycyclic-Fused Skeletons from the Endophytic Fungus Phomopsis sp. shj2.

Phomopchalasins A (1) and B (2), two novel cytochalasans with unprecedented carbon skeletons, and phomopchalasin C (3), containing a rare hydroperoxyl motif, were obtained from the endophytic fungus Phomopsis sp. shj2, which was first isolated from the Isodon eriocalyx var. laxiflora. Their structures were elucidated by extensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and X-ray crystallographic analysis. Notably, 1 possessed an unprecedented 5/6/5/8-fused tetracyclic ring system, and 2 featured a novel 5/6/6/7/5-fused pentacyclic skeleton. The cytotoxic, anti-inflammatory, and antimigratory activities of 1-3 were evaluated in vitro.

Bioactive Enmein-Type ent-Kaurane Diterpenoids from Isodon phyllostachys.

Thirty-two enmein-type ent-kaurane diterpenoids, including 13 new compounds, were isolated from the aerial parts of Isodon phyllostachys. Compounds 1 and 2 are the first examples of 3,20:6,20-diepoxyenmein-type ent-kauranoids, and the structures of these new compounds were established mainly by analyzing NMR and HREIMS data. The absolute configurations of 1 and 8 and the relative configuration of 9 were determined using single-crystal X-ray diffraction. Compounds 11, 15, 20, and 21 were active against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), with IC50 values ranging from 1.2 to 5.0 µM. Compounds 3, 11, 15, 17, 20, 21, 25, and 29 strongly inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 0.74 to 4.93 µM.

Acylated neo-clerodane type diterpenoids from the aerial parts of Scutellaria coleifolia Levl. (Lamiaceae).

Twenty new neo-clerodane type diterpenoids, scutefolides G1-S (1-20), were isolated from the 70 % aqueous acetone extract of the aerial parts of Scutellaria coleifolia. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of 1, 2, 7, 8, 14 and 15 were determined by means of the CD exciton chirality method. Compounds 1, 2, 5, 7, 8, 12, 14, 15, 18 and 19 were evaluated for their cytotoxic activities against four human cancer cell lines, and anti-bacterial activities against methicillin-resistant Staphylococcus aureus.

Triterpenoids from Schisandra propinqua var. propinqua.

Four new triterpenoids, propindilactone T (1), propindilactone U (2), changnanic acid 3-methyl ester (3) and schipropinic. acid (4), together with five known ones (5-9), were isolated and identified from the stems and leaves of Schisandra propinqua var. propinqua; their structures were determined based on spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was confirmed by X-ray analysis. Compounds 1, 2, and 4-9 were tested for their cytotoxic activities against five human tumor cell lines; all were inactive except for 8, which showed weak activity against some of the cell lines.

Antiviral sesquiterpenes from leaves of Nicotiana tabacum.

Three unreported sesquiterpenes possessing two new skeletons, tabasesquiterpenes A-C (1-3), together with three known sesquiterpenes (3-6) were isolated from the leaves of Nicotiana tabacum. Their structures were determined mainly by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1-6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 35.2%, which were higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 20.5-28.6%.

Kadcoccinic Acids A-J, Triterpene Acids from Kadsura coccinea.

Eleven triterpene acids including 10 new compounds (kadcoccinic acids A-J, 1-10) were isolated from the stems of Kadsura coccinea. Except for 10, these compounds feature a rearranged lanostane skeleton with a 6/6/5/6 tetracyclic ring system, and compounds 1 and 2 are the first examples of 2,3-seco-6/6/5/6-fused tetracyclic triterpenoids. Their structures were established primarily by spectroscopic and spectrometric methods. Additionally, the absolute configuration of 3 was determined by single-crystal X-ray diffraction. Several of the compounds isolated were tested for their anti-HIV-1 and cytotoxic activities.

Acylated neo-clerodanes and 19-nor-neo-clerodanes from the aerial parts of Scutellaria coleifolia (Lamiaceae).

Scutefolides A1 and A2, two acylated neo-clerodanes with a 19,18-γ-lactone, scutefolides B1, B2 and C, three 19-nor-neo-clerodanes, together with scutefolides D, E1, E2 and F, four neo-clerodanes, were isolated from the EtOAc-soluble fraction of the aerial parts of Scutellaria coleifolia. Their structures were established on the basis of spectroscopic analysis. The absolute configurations of four of these compounds were elucidated by the CD exciton chirality method. Cytotoxic activities of scutefolides D-F against four cancer cell lines (KB, A549, HeLa, and MCF7) were also evaluated, but they were inactive.

Six new cytotoxic and anti-inflammatory 11, 20-epoxy-ent-kaurane diterpenoids from Isodon wikstroemioides.

The present study was designed to determine the chemical constituents of EtOAc extracts of the aerial parts of Isodon wikstroemioides. Compounds 1-8 were isolated and purified by normal-phase silica gel and reversed-phase C18silica gel column chromatography and HPLC. Their structures were elucidated by extensive spectroscopic methods. Most of them were evaluated for their in vitro cytotoxicity against human cancer HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cells and their inhibitory activity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages. Among the eight 11, 20-epoxy-ent-kauranoids isolated, compounds 1-6 (isowikstroemins H-M) were new diterpenoids. Compounds 1, 3, and 7 exhibited significant cytotoxicity with IC50 values ranging from (0.84 ± 0.02) to (4.09 ± 0.34) µmol · L(-1), while compounds 4 and 5 showed selective cytotoxicity. In addition, compounds 1, 3, 4, and 7 exhibited inhibitory activity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages. These results provide a basis for future development of these compounds as anti-cancer and anti-inflammatory agents.

Diterpene alkaloids with an aza-ent-kaurane skeleton from Isodon rubescens.

Two compounds belonging to a new group of diterpene alkaloids, kaurines A and B (1 and 2), and an alkaloid bearing a succinimide moiety (3) were obtained from Isodon rubescens. Their structures and absolute configurations were determined by spectroscopy and quantum-chemical computational (13)C NMR and ECD data analysis. These alkaloids differ from known diterpene alkaloids and diterpenoids and are presumably biosynthesized from ent-kaurane diterpenoids.

Unusual cycloartane triterpenoids from Kadsura ananosma.

Five 3,4-seco-cycloartane triterpenoids were isolated from the stems of Kadsura ananosma, two of which had rearranged 5/6 consecutive carbocycle rings C/D (trivially named ananosins A (1) and B (2)), one had a migrated CH3-18 (named ananosins C (3)), and two were analogs, ananosins D (4) and E (5). Their structures were characterized by comprehensive spectroscopic analysis, especially using 2D NMR spectra. A biogenetic pathway to 1 was proposed. These 5 compounds, together with 5 known analogs isolated from the same origin, were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549, PANC-1, and SK-BR-3 human cancer cells, but were inactive.

Heterodimeric ent-kauranoids from Isodon tenuifolius.

Thirteen new heterodimeric ent-kauranoids, bistenuifolins A-M (1-13), were isolated from the aerial parts of Isodon tenuifolius. The constituent units of compounds 1-6 were linked by a six-membered dihydropyran ring, while those of compounds 7-11 were joined by a rare single carbon-carbon bond (C-16→C-17'). The constituent units of 12 and 13 were linked via an unusual cyclobutane moiety. The structures of these metabolites were established via spectrometric analyses, and the absolute configurations of 1 and 4 were defined by single-crystal X-ray diffraction. Selected compounds were evaluated for their cytotoxicity against a small panel of human tumor cell lines; bistenuifolin B (2) exhibited weak inhibitory effects.