Spiroligustolides A and B: Two pairs of enantiomeric spiro-orthoester-containing phthalide dimers as Cav3.1 calcium channel inhibitors from Ligusticum Chuanxiong Hort.

Two pairs of unprecedented enantiomeric phthalide dimers, spiroligustolides A (1a/1b) and B (2a/2b), featuring a unique spiroorthoster linkage between two monomeric units to form a 5/6/5/6/6-fused ring system, were isolated from the roots of Ligusticum chuanxiong. The structures and relative configurations of 1 and 2 were determined by HR-ESI-MS, IR, and NMR spectroscopic data, coupled with single-crystal X-ray diffraction analysis, and the absolute configurations of 1a, 1b, 2a, and 2b were established by comparing the experimental and calculated electronic circular dichroism (ECD) data. Plausible biosynthetic pathway for 1 and 2 was proposed. Moreover, compounds 1, 1b, and 2b showed remarkable inhibitory activities on Cav3.1 calcium channel with IC50 values of 8.34, 7.08, and 8.60 µM, respectively.

Hupertimines A-E, Fawcettimine-Type Lycopodium Alkaloids from Huperzia serrata.

Five new fawcettimine-type Lycopodium alkaloids, hupertimines A-E (1-5), were discovered from the whole plant of Huperzia serrata, along with two known alkaloids, 8α-hydroxyphlegmariurine B (6) and 8ß-hydroxyphlegmariurine B (7). The structures of 1-7 were identified through HR-MS, IR, 1 H, 13 C, and 2D NMR, and single-crystal X-ray diffraction analysis. Structurally, compound 1 was the fourth example of Lycopodium alkaloid with an ether linkage between C-5 and C-13 and 2 was the third example of Lycopodium alkaloid with a 5/5/5/5/6 pentacyclic ring system and featuring a 1-aza-7-oxabicyclo[2.2.1]heptane unit. Compounds 1-7 were tested for their BACE1 inhibitory activity. In addition, the correct 1 H- and 13 C-NMR data for 7 were reported in current study.

Four Highly Oxygenated Sesquiterpenoids from the Fruits of Illicium micranthum Dunn.

Four highly oxygenated sesquiterpenoids, illimicranolides A (1) and B (2), and illicinolides E (3) and F (4), were obtained from the fruits of Illicium micranthum Dunn, as well as one known analog, illicinolide B (5). The chemical structures of 1-4 were determined comprehensively by 1D (1 H and 13 C) and 2D (HMBC, HSQC, 1 H-1 H COSY, and ROESY) NMR, and HR-ESI-MS data. Structurally, compound 1 was an unprecedented sesquiterpenoid with a 5/5/6/5-fused tetracyclic ring system and was the first seco-prezizaane sesquiterpenoid featuring a 11,8-γ-lactone ring. Compounds 3 and 4 were the fifth and sixth examples of illicinolide-type sesquiterpenoids. Moreover, compound 1 demonstrated neurotrophic activity of NGF-induced PC12 cells with differentiation rate of 10.34 % at a concentration of 10 µM.

seco-Prezizanne Sesquiterpenes and Prenylated C6-C3 Compounds from the Fruits of Illicium lanceolatum A. C. Smith.

Two new seco-prezizaane-type sesquiterpenes, 2ß-hydroxy-6-deoxyneoanisatin (1) and 3,4-anhydro-2-oxo-1α-hydroxy-6-deoxyneoanisatin (2), and two new prenylated C6 -C3 compounds, illilanceofunones A (3) and B (4), were obtained from the fruits of Illicium lanceolatum, along with four known prenylated C6 -C3 compounds (5-8). Their structures were proposed through HR-ESI-MS, 1 H, 13 C, and 2D NMR data interpretation. Moreover, the absolute configuration of 1 and 2 were further assigned by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD) calculations, respectively. Illihenryipyranol A (6) exhibited neuroprotective activity against MPP+ -induced PC12 cell damage in a dose-dependent manner.

Spirocyclohexadienone-Type Neolignans with Neuroprotective and Neurite Outgrowth Enhancing Activities from Magnolia liliiflora.

Three rare spirocyclohexadienone-type neolignans, magnoflorins A-C (1-3), and three known analogs (4-6), were isolated from the leaves of Magnolia liliiflora. Magnoflorin D (4) was obtained from natural resources for the first time. The chemical structures and absolute configurations of 1-4 were elucidated through detailed analysis of HR-ESI-MS, IR, 1 H, 13 C, and 2D NMR, and ECD experiments. The absolute configuration of 5 were characterized by X-ray crystallography in present study. Moreover, compounds 4 and 5 displayed moderate neuroprotective activity against corticosterone-induced PC12 cells injury at 20 µM with cell viability of 71.5±0.99 % and 73.0±1.42 %, respectively, compared to the model group with 60.83±0.93 %. Compound 6 could enhance neurite outgrowth of nerve growth factor (NGF)-induced PC12 cells at 10 µM with the differentiation rate of 11.98 %, compared with 20.49 % of 50 ng/ml NGF.

Discovery of pseudolaric acid A as a new Hsp90 inhibitor uncovers its potential anticancer mechanism.

Pseudolaric acid A (PAA), one of the main bioactive ingredients in traditional medicine Pseudolarix cortex, exhibits remarkable anticancer activities. Yet its mechanism of action and molecular target have not been investigated and remain unclear. In this work, mechanistic study showed that PAA induced cell cycle arrest at G2/M phase and promoted cell death through caspase-8/caspase-3 pathway, demonstrating potent antiproliferation and anticancer activities. PAA was discovered to be a new Hsp90 inhibitor and multiple biophysical experiments confirmed that PAA directly bind to Hsp90. Active PAA-probe was designed, synthesized and biological evaluated. It was subsequently employed to verify the cellular interaction with Hsp90 in HeLa cells through photoaffinity labeling approach. Furthermore, NMR experiments showed that N-terminal domain of Hsp90 and essential groups in PAA are important for the protein-inhibitor recognition. Structure-activity relationship studies revealed the correlation between its Hsp90 inhibitory activity with anticancer activity. This work proposed a potential mechanism involved with the anticancer activity of PAA and will improve the appreciation of PAA as a potential cancer therapy candidate.

Neo-clerodane Diterpenoids with Hypoglycemic Effects in Vivo from the Aerial Parts of Salvia hispanica L.

A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).

Tetranorlanostane and Lanostane Triterpenoids with Cytotoxic Activity from the Epidermis of Poria cocos.

Two unprecedented tetranorlanostane triterpenoids, poricolides A (1) and B (2), and two new lanostane triterpenoids, 3ß-acetoxy-24-methyllanosta-8,16,24(31)-trien-21-oic acid (3) and 3ß-acetoxylanosta-7,9(11),16,23-tetraen-21-oic acid (4), were isolated from the epidermis of Poria cocos. The structures of 1-4 were determined via analysis of 1 H-, 13 C-, and 2D-NMR, and HR-ESI-MS data, and the absolute configurations of 1 and 3 were established by single-crystal X-ray diffraction analysis. Compounds 1 and 2 were the first report of tetranorlanostane triterpenoid having a δ-lactone ring at C(17). Compounds 3 and 4 were rare lanostane triterpenoids having a double bond between C(16) and C(17). Compounds 1-4 exhibited potent antiproliferative effects against A549, SMMC-7721, MCF-7, and SW480 cancer cell lines with IC50 values from 16.19±0.38 to 27.74±1.12 µM.

Monoterpene Indole Alkaloids with Cav3.1 T-Type Calcium Channel Inhibitory Activity from Catharanthus roseus.

Catharanthus roseus is a well-known traditional herbal medicine for the treatment of cancer, hypertension, scald, and sore in China. Phytochemical investigation on the twigs and leaves of this species led to the isolation of two new monoterpene indole alkaloids, catharanosines A (1) and B (2), and six known analogues (3-8). Structures of 1 and 2 were established by 1H-, 13C- and 2D-NMR, and HREIMS data. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 2 represented an unprecedented aspidosperma-type alkaloid with a 2-piperidinyl moiety at C-10. Compounds 6-8 exhibited remarkable Cav3.1 low voltage-gated calcium channel (LVGCC) inhibitory activity with IC50 values of 11.83 ± 1.02, 14.3 ± 1.20, and 14.54 ± 0.99 µM, respectively.

Huperserratines A and B, Two Macrocyclic Lycopodium Alkaloids with an Unusual Skeleton from Huperzia serrata.

Huperserratines A (1) and B (2), two Lycopodium alkaloids with an unprecedented 5-aza-bicyclo[10.4.0]hexadecane skeleton and an oxime function, were isolated from Huperzia serrata. Their structures including absolute configurations were determined by extensive NMR spectroscopic and X-ray diffraction analysis. Compounds 1 and 2 were the first examples of macrocyclic Lycopodium alkaloids with an aza-12-membered ring. A plausible biogenetic pathway of these compounds was also proposed. Compound 1 exhibited moderate anti-HIV-1 activity with an EC50 of 52.91 µg/mL and a therapy index greater than 3.78.

Caesalpanins A-C, Three Dimeric Cassane Diterpenoids from the Seeds of Caesalpinia sappan L.

Three dimeric cassane diterpenoids, caesalpanins A-C, were isolated from the seeds of Caesalpinia sappan L., as well as three known compounds. Their structures were determined via analysis of 1D-, 2D-NMR, and HR-ESI-MS data. Caesalpanins A and B were the second and third compounds that presented a nitrogen-containing cassane diterpenoid dimer linked through one ether bond between C-19 and C-20'. Caesalpanin B exhibited moderate cytotoxic activity against MCF-7 cell lines with IC50 value of 29.98 µm. Caesalpanins A and B had weak inhibitory effects against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages at 50 µm with inhibitory rate of 36.01 % and 32.93 %, respectively.

Phlegmadine A: A Lycopodium Alkaloid with a Unique Cyclobutane Ring from Phlegmariurus phlegmaria.

Phlegmadine A (1), a Lycopodium alkaloid with a unique cyclobutane ring and featuring a complex tetracyclo[4.2.2.03,8.03,10]decane-bridged system, together with three biogenetically related known compounds, was isolated from the Phlegmariurus phlegmaria. The structures and absolute configurations of 1 and 2 were determined by NMR and single-crystal X-ray analysis. Among them, compound 2 exhibited noticeable protective effects for long-term potentiation impairment by corticosterone induced in mice. Moreover, we succeeded in the efficient synthesis of 1 from 3 by a biomimetic synthesis method.

Sesquiterpenes from the Leaves of Magnolia delavayi Franch. and Their Cytotoxic Activities.

Thirteen sesquiterpenes including eight new ones, magnodelavins A-H (1-8), were obtained from the 95 % ethanolic extract of the leaves of Magnolia delavayi Franch. The structures of the new compounds were determined by exhaustive 1 H-, 13 C-, 2D-NMR, UV, IR, and HR-ESI-MS data, as well as X-ray crystallographic analysis. Compounds 9 and 10 showed potent cytotoxic activities against HL-60, A-549, SMMC-7721, MCF-7, and SW480 human cancer cell lines in vitro using MTS assay.

Three new Lycopodium alkaloids from Lycopodium japonicum.

Three new Lycopodium alkaloids (1-3), together with 15 known alkaloids, were isolated from club moss Lycopodium japonicum. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR spectra. Compound 1 has an unusual ß-oriented methyl group substituted at C-15 and an α-hydroxy cyclopentenone moiety. All new alkaloids were evaluated for the inhibition of T-type calcium channel.

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

Activity-guided fractionation strategy was used to investigate chemical constituents from the roots of Podocarpus macrophyllus. Successfully, two new norditerpenes, 2ß-hydroxymakilactone A (1) and 3ß-hydroxymakilactone A (2), along with ten known analogues (3 - 12) were isolated. The structures of 1 and 2 were elucidated by spectroscopic analysis including 1D-, 2D-NMR, and HR-ESI-MS data. The previously reported structure of 2,3-dihydro-2α-hydroxypodolide was revised as 2,3-dihydro-2ß-hydroxypodolide (3) by spectroscopic analysis, and was further confirmed by X-ray crystallographic analysis. Cytotoxic activities of all isolated compounds against five human solid tumour cell lines (AGS, HeLa, MDA-MB-231, HepG-2, and PANC-1) were evaluated. All of them exhibited anti-proliferative activities (IC50  = 0.3 - 27 µm), except for 10. Compounds 1, 4, 5, 6, and 8 exhibited potent inhibitory activities with IC50  < 1 µm against HeLa and AGS cells.

Vibsane-Type Diterpenoids from Viburnum odoratissimum and Their Cytotoxic and HSP90 Inhibitory Activities.

Four new vibsane-type diterpenoids, vibsanol I (1), 15-hydroperoxyvibsanol A (2), 14-hydroperoxyvibsanol B (3), 15-O-methylvibsanin U (4), and a new natural product, 5,6-dihydrovibsanin B (5), as well as six known analogues, were isolated from the twigs and leaves of Viburnum odoratissimum. Their structures were elucidated by spectroscopic analyses and chemical derivatization method. All compounds showed different levels of cytotoxicity against five cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480). Remarkably, 14,18-O-diacetyl-15-O-methylvibsanin U (4a) showed significant cytotoxicity against HL-60, A-549, SMMC-7721, MCF-7, and SW480, with IC50 values of 0.15 ± 0.01, 0.69 ± 0.01, 0.41 ± 0.02, 0.75 ± 0.03, and 0.48 ± 0.03 µm, respectively. In addition, vibsanin K (10) was identified as a HSP90 inhibitor with an IC50 value of 19.16 µm.

Hypofolins A - L, ent-Labdane Diterpenoids from the Roots of Hypoestes phyllostachya 'Pink Splash'.

Twelve new ent-labdane diterpenoids, hypofolins A - F (1 - 6) and hypofolins G - L (7a/7b, 8a/8b, and 9a/9b), were isolated from the roots of Hypoestes phyllostachya 'Pink Splash'. Their structures were elucidated by extensive 1D- and 2D-NMR spectroscopic and HR-MS data. The absolute configurations of 1, 2, 5, and 7a/7b were determined by single crystal X-ray diffraction and ECD analysis, as well as chemical transformations. Compounds 7a/7b, 8a/8b, and 9a/9b were isolated as three pairs of interconverting mixture of two isomers between ketone and hemiketal types. Compound 1 showed weak cytotoxicity against SMMC-7721 cell line with IC50 value of 31.40 µm.

Guaiane-Type Sesquiterpenoids from Alismatis Rhizoma and Their Anti-inflammatory Activity.

Twelve guaiane-type sesquiterpenoids, including four new ones, 10-O-methyl-orientalol A (1), 10-O-ethyl-alismoxide (2), 3ß,4ß-expoxy-chrysothol (3), orientalol G (4), and a new norsesquiterpenoid, orientalol H (5), were isolated from Chinese Alismatis Rhizoma, the dried rhizome of Alisma orientale. The structures of new compounds were elucidated on the basis of spectroscopic data. Moreover, the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells of all compounds was tested.

Protostane-Type Triterpenoids from Alisma orientale.

Twenty-eight protostane triterpenoids, including a new degraded one (1), nine new ones (2 - 10), and two new natural ones (11 and 12), have been isolated from the dried rhizomes of Alisma orientale. Alisol R (1) was the first 20,21,22,23,24,25,26,27-octanorprotostane triterpenoid. The absolute configurations of 25-methoxyalisol F (2) and 16ß-hydroperoxyalisol B 23-acetate (3) were determined by X-ray diffraction analysis. In addition, alismaketone-B 23-acetate (28) showed potent vasorelaxant activity on endothelium-intact thoracic aorta rings precontracted with KCl.

Sesquiterpenoids from the twigs and leaves of Fokienia hodginsii.

A rare carotane-type sesquiterpenoid, forkienin A (1), a new eudesmane-type sesquiterpenoid, forkienin B (2), and a new natural eudesmane-type sesquiterpenoid, forkienin C (3), were isolated from the twigs and leaves of Fokienia hodginsii, along with eight known sesquiterpenoids. The structures of the new compounds were elucidated on the basis of their spectroscopic analysis, including 1D and 2D NMR methods. All compounds were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines.