Phainanolide A (1), a highly modified triterpenoid incorporating an unprecedented 6/9/6 heterotricyclic system and a highly oxygenated 5,5-spirocyclic ketal lactone, along with three new triterpenoids 2–4 were isolated from Phyllanthus hainanensis. Their structures were completely elucidated by a combination of diverse methods including 2D NMR, quantum chemical NMR and ECD calculations, and NMR data analogy with model compounds. Compounds 1–4 exhibited both remarkable cytotoxic and immunosuppressive activities.

Four limonoids, triconoids A–C (1–3) possessing a new rearranged mexicanolide skeleton and triconoid D (4) furnishing a new rearranged 1,2-seco-phragmalin skeleton, were isolated from the Nepalese plant Trichilia connaroides. Two rearranged limonoid skeletons sharing an F ring of methyl 5-oxotetrahydrofuran-2-carboxylate were postulated to be formed biosynthetically via a very unique chemical cascade. Their structures were fully accomplished by spectroscopic data, single-crystal X-ray diffraction, and electrostatic circular dichroism analysis.

Five new diterpenoids including two Cephalotaxus troponoids (1 and 2), two 17-nor-cephalotane-type diterpenoids (3 and 4), and an abietane-type diterpenoid (5), two new lignans (6 and 7), and a new trisnorneoligan (8) along with eight known compounds were identified from the twigs and leaves of Cephalotaxus fortunei. The structure of 11-hydroxyhainanolidol was revised as 10-hydroxyhainanolidol (9) by X-ray crystallographic data. Compounds 3 and 4 are the first examples of 17-nor-cephalotane-type diterpenoids that are likely the biosynthesis precursors of the co-occurring troponoids (e.g., 1, 2, and 9). Compound 1 exhibited cytotoxic activities against HL-60 and A-549 cells with IC50 values of 0.77 ± 0.05 and 1.129 ± 0.057 μM, respectively.

Inspired by the discovery of the antimalarial drug artemisinin from a traditional Chinese medicine (TCM), a natural product library of 44 lindenane-type sesquiterpenoids was assessed for activities against the Dd2 chloroquine-resistant strain of the malaria parasite Plasmodium falciparum. These compounds were mainly isolated from plants of the Chloranthus genus, many species of which are named “Sikuaiwa” in TCM and have long been used to treat malaria. The compounds consisted of 41 sesquiterpenoid dimers and three monomers, including the 12 new dimers 1–12 isolated from Chloranthus fortunei. The results showed that 16 dimers exhibited potent antiplasmodial activities (<100 nM); in particular, compounds 1, 14, and 19 exhibited low nanomolar activities with IC50 values ranging from 1 to 7 nM, which is comparable to the potency of artemisinin, and selectivity index values toward mammalian cells greater than 500. A comprehensive structure–activity relationship study indicated that three functional groups are essential and two motifs can be modified.

Three dimeric sesquiterpenoids (1–3), fortunoid A (1) possessing a new carbon skeleton of rearranged lindenane dimer and fortunoids B (2) and C (3) representing the first example of the dimers of a lindenane and a eudesmane sesquiterpene, were isolated from Chloranthus fortunei. Their structures with absolute configurations were established by spectroscopic data and electric circular dichroism analysis. Their biosynthetic origins were also proposed. Compounds 1 and 2 showed moderate antimalarial activities.

All eight stereoisomers (1–8) of a neosecurinane-type Securinega alkaloid were isolated and identified from a Chinese medicinal plant, Flueggea virosa. Structures of the four pairs of enantiomers were characterized and differentiated from one another based on comprehensive spectroscopic analyses especially specific optical rotation and electronic circular dichroism measurements. While clarifying some historical ambiguities, the discovery of these molecules also brings new puzzles to the natural products community, which will be surely leading to further attention and studies. This case investigation also reminds that future researchers who work with natural products should pay more attention to the enantiomeric purity of their samples.Download high-res image (170KB)Download full-size image

•Trigochinins A–C (1–3) are three highly oxygenated daphnane-type diterpenes.•The absolute configuration of 1 was confirmed by X-ray crystallography study.•The absolute configurations of 2 and 3 were confirmed by theoretical ECD study.Trigochinins A–C (1–3) are three highly oxygenated daphnane-type diterpenes isolated from Trigonostemon chinensis. Their structures with the absolute configurations were initially assigned by a combination of spectroscopic data, X-ray crystallography (Mo Kα radiation) study and CD analysis. In the current study, the absolute configurations of trigochinins A–C were confirmed by single crystal X-ray diffraction (Cu Kα radiation) study, CD spectral analogy, and theoretical ECD study by using quantum chemical TDDFT calculations.Download high-res image (86KB)Download full-size image

Chemical investigation into the alkaloidal constituents of the Nepalese Daphniphyllum himalense has returned two new compounds, himalensines A (1) and B (2), with unprecedented carbon skeletons. Structures of the two alkaloids have been characterized on the basis of spectroscopic methods, especially via 2D NMR data analysis. Himalensine B (2) showed marginal inhibitory activities against two kinases, PTP1B and IKK-β.

Four limonoids, cipacinoids A–D (1–4), with spirocyclic skeletons were isolated from Cipadessa cinerascens. It is particularly notable that compounds 1–3 had a 17S-configuration for the first time in the limonoid family. Their structures with absolute configurations were assigned by spectroscopic data, X-ray crystallography, and CD analysis. Compound 1 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibition.

Three new diterpenoids, mannolides A–C (1–3), and two new Cephalotaxus troponoids, 4 and 5, were isolated from Cephalotaxus mannii and structurally characterized by spectroscopic data and X-ray crystallography. The discovery of compounds 1–3 featuring a new intact carbon skeleton, proposed as cephalotane, sheds new light on the biogenesis of Cephalotaxus troponoids, a rare class of antitumor C19 norditerpenoids. Antitumor tests showed that the tropone motif is essential for the activity.

Three new ring B-seco limonoids, ciliatonoids A–C (1–3), were isolated from Toona ciliate and structurally characterized by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Ciliatonoids A and B feature an unprecedented limonoid architecture, while ciliatonoid C belongs to a rare class of limonoids. Biological evaluation showed that compound 3 exhibited modest activities against the tested tumor cell lines.

Nine new cedrelone-type limonoid derivatives, walsunoids A–I (1–9), and 11 known compounds were isolated from the leaves of Walsura robusta. Walsunoid A (1) is a new degradation product of cedrelone-type limonoids, and walsunoid I (9) is a rare cedrelone-type limonoid amide. Their structures and absolute configurations were determined by spectroscopic data, single-crystal X-ray diffraction, and ECD data analyses. Five compounds showed moderate inhibitory activities against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC50 values ranging from 0.69 to 9.9 μM.

Aqueous ethanol extracts of powdered twigs of Euphorbia esula afforded 16 new diterpenoids, named euphorbesulins A–P. These euphorbesulins included presegetane (1–3), jatrophane (4–14), paraliane (15), and isopimarane (16) diterpenoids as well as six known analogues. Compounds 1–3 represent a rare type of presegetane diterpenoid. Their structures were determined by analysis of the spectroscopic data, and the absolute configuration of 1 was established by X-ray crystallography. Diterpenoid 7 showed low nanomolar antimalarial activity, while the remaining compounds showed only moderate or no antimalarial activity.

Nine new conjugates of sesquiterpenoids and acylphloroglucinols, named eucarobustols A–I (1–9), as well as 11 known analogues were isolated from the leaves of Eucalyptus robusta. The sesquiterpenoid motifs furnishing the new conjugates included four structural types of aristolane (1 and 2), guaiane (3), eudesmane (4), and aromadendrane (5–9) moieties. Compounds 1 and 2 were found to represent the first examples of conjugates of aristolane and acylphloroglucinol units. In turn, compound 3 features a new coupling model of guaiane and acylphloroglucinol via the C-4–C-7′ bond. Compounds 1, 7, and 9 showed inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 1.3, 1.8, and 1.6 μM, respectively.

Chemical investigation into the minor constituents of Aphanamixis grandifolia yielded three new diterpenoid dimers, aphadilactones E–G (1–3) featuring a new carbon skeleton. Their structures and absolute configurations were fully established by comprehensive spectroscopic data analysis and ECD calculation. Discovery of another two new dimers (4 and 5) suggested the structure of recently reported aphanamene A to be re-investigated. Compounds 1–5 showed moderate antimalarial activities with low micromolar IC50 values.

Nine new Daphniphyllum alkaloids (1–9) and 16 biosynthetically related known ones were obtained during the phytochemical investigation into a Nepalese plant, Daphniphyllum himalense. Structures were assigned to these compounds based on careful spectroscopic interpretation and NMR comparison with literature data. Deuteration of H2-16 in CD3OD due to quick keto-enol tautomerization was observed for both 2 and 3. The recently reported 3β-hydroxydaphniyunnine A was re-examined and its structure was revised to be 21-deoxymacropodumine D via X-ray diffraction analysis. All the isolates were screened preliminarily for their in vitro inhibitory effects against four kinases, PTP1B, aurora A, HDAC6 and IKK-β, and selective alkaloids exhibited weak activities at 20 μg mL−1.

The strained cyclopropane and/or cyclobutane subunits occurred in many complex natural products including terpenoids, steroids and alkaloids. Natural products with cyclopropane and/or cyclobutane motifs not only furnished fascinating structures, but also exhibited versatile biological activities, such as cytotoxic, anti-HIV, antimicrobial, antiviral, and immunosuppressive effects. This review covered a large array of structurally unique natural products with strained cyclopropane and/or cyclobutane motifs and summarized their structural features, distributions, biological activities, as well as biogenetic considerations.

Three new halimane-type diterpenoids formosins A–C (1–3), and three clerodane-type diterpenoids formosins D–F (4–6), were isolated from the twigs of Excoecaria formosana. Their structures were assigned on the basis of spectroscopic data analysis. Compounds 1 and 4 showed moderate anti-microbial activities against Bacillus subtilis (MIC = 50 and 50 μg/mL, respectively). Compound 6 exhibited moderate anti-microbial activities against two strains of Helicobacter pylori (Hp-SS1 and ATCC 43504) with MIC values of 50 and 50 μg/mL, respectively.

Two new alkaloids, flueggether A (1) and virosinine A (2), were isolated from a Chinese medicinal plant, Flueggea virosa. Their structures were assigned via spectroscopic methods with the absolute configurations of 1 and 2 being established by X-ray diffraction analysis and calculated electronic circular dichroism data, respectively. Compound 1 represents the first example with an ether bridge of Securinega alkaloid oligomers, and 2 bears a new heterocyclic backbone. Both alkaloids showed mild in vitro anti-HIV activity.

Thirteen new limonoids, dysoxylumosins A–M (1–13), along with six known analogues (14–19) were isolated from the twigs of Dysoxylum mollissimum. Their structures were established on the basis of spectroscopic data analysis. Compounds 1–6, 8, and 12 exhibited significant inhibitory activities against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Dysoxylumosin F (6), the most potent substance isolated, showed an IC50 value of 9.6 ± 0.90 nM against human 11β-HSD1.

Sixteen new limonoids, named ciparasins A–P (1–16), comprising three structural categories of trijugin-type (1–7), cipadesin-type (8–15), and prieurianin-type (16) compounds, as well as 15 known limonoid analogues (17–31), were isolated from Cipadessa cinerascens. Ciparasins E–G (5–7) were found to possess a rare γ-hydroxylbutenolide moiety at C-17. Ciparasins B (2) and P (16) showed significant anti-HIV activities, with EC50 values of 5.5 ± 0.6 (SI >7.2) and 6.1 ± 0.7 (SI >6.5) μM, respectively.

Seven new limonoids, dysomollides A–G (1–7), and two new cycloapotirucallane-type triterpenoids, dysomollins A and B (8 and 9), together with three known compounds, dysoxylumin A (10) and toonapubesins A (11) and B (12), were isolated from the twigs of Dysoxylum mollissimum var. glaberrimum. The structures of 1–9 were elucidated on the basis of spectroscopic methods. Compound 10 showed inhibitory activity against A549 cells with an IC50 value of 2.1 μM, and compound 11 exhibited activity against P388 cells with an IC50 value of 6.7 μM.

Thirteen new hydroxylated calyciphylline A-type Daphniphyllum alkaloids (1–13) were isolated from an ethanolic extract of Daphniphyllum himalense. These structures were characterized on the basis of spectroscopic data analysis, especially from their 2D NMR spectra. Oxidation at the C-3, C-9, C-11, and C-12 positions is reported for the first time for this class of compounds. Selective compounds showed low inhibitory rates against three kinase enzymes, PTP1B, aurora A, and IKK-β, at a concentration of 20 μg/mL.

A search for 11β-HSD1 inhibitors from Ricinodendron heudelotii has afforded seven new tetracyclic triterpenoids ricinodols A–G (1–7), along with three known podocarpane-type diterpenoids (8–10). Ricinodols A (1) and B (2) possess a new carbon skeleton with a novel concurrent rearrangement of Me-19 (10 → 9) and Me-30 (14 → 8). Their structures were elucidated by comprehensive spectroscopic analyses and comparison with reported analogues, while the 24R-configuration of those with a 24-OH group was established by an in situ dimolybdenum CD method. Of these isolates, ricinodol E (5) exhibited the best inhibitory activities against both human and mouse 11β-HSD1 with IC50 values of 0.36 ± 0.26 and 0.84 ± 0.18 μM, respectively.

Chemical fractionation of the ethanolic extract of Flueggea virosa yielded a group of Securinega alkaloids including flueggenines E (1) and F (2) as novel hybrid structures, flueggenines G–I (3–5) as new dimers and fluevirosines E–H (6–9) as new trimers, along with six known biosynthetically related compounds. The diverse structures of these isolates were characterized via comprehensive spectroscopic analyses and comparison with literature data. Compounds 1 and 2 are rare Securinega alkaloid hybrids incorporating tryptamine and piperidine residues, respectively, while 3 represents the first example bearing a securinine-type monomeric unit among Securinega alkaloid dimers. An in vitro anti-HIV screening of all available alkaloids revealed weak to moderate activities for over half of these isolates with EC50 values ranging from 7.8 to 122 μM. Among the tested compounds, the known dimer flueggenine D exhibited the best activity with an EC50 of 7.8 ± 0.8 μM.

An MS guided fractionation of the alkaloidal constituents of Flueggea virosa has yielded nine new Securinega alkaloid oligomers, fluevirosinines B–J (1–9). The absolute structures of these oligomers have been characterized on the basis of spectroscopic data and biogenetic consideration. Fluevirosinines B–E (1–4) are four tetramers with new connecting sequences or new oligomerizing patterns, and fluevirosinines G–J (6–9) represent the first examples of pentamers of the Securinega alkaloid family. Among these alkaloids, fluevirosinine B (1) showed the best anti-HIV activity with an EC50 value of 14.1±1.2 μM.

Chemical study on the twigs and leaves of Croton tiglium has led to the isolation of 11 new tigliane-type diterpenoids, crotignoids A–K (1–11), along with eight known analogues (12–19). The structures of these compounds were elucidated on the basis of detailed spectroscopic analysis. In vitro cytotoxic assays revealed moderate inhibition of compounds 1–10 toward human HL-60 and A549 tumor cells, with 1 exhibiting the strongest activity against HL-60 cell line with an IC50 value of 1.61 μM.

Logeracemin A (1), the first Daphniphyllum alkaloid dimer featuring an unprecedented carbon skeleton with a unique conjugated trispiro[4,5] decane backbone, was isolated from Daphniphyllum longeracemosum. Its structure and absolute configuration were established on the basis of spectroscopic data and X-ray crystallography. Logeracemin A showed significant anti-HIV activity with an EC50 of 4.5 ± 0.1 μM and a selectivity index of 6.2. The structure–activity relationship of the tested compounds was briefly discussed.

Phainanoids A–F (1–6), six highly modified triterpenoids with a new carbon skeleton by incorporating two unique motifs of a 4,5- and a 5,5-spirocyclic systems, were isolated from Phyllanthus hainanensis. Their structures with absolute configurations were determined by spectroscopic data, chemical methods, and X-ray crystallography. Compounds 1–6 exhibited exceptionally potent immunosuppressive activities in vitro against the proliferation of T and B lymphocytes. The most potent one, phainanoid F (6), showed activities against the proliferation of T cells with IC50 value of 2.04 ± 0.01 nM (positive control CsA = 14.21 ± 0.01 nM) and B cells with IC50 value of <1.60 ± 0.01 nM (CsA = 352.87 ± 0.01 nM), which is about 7 and 221 times as active as CsA, respectively. The structure–activity relationships of 1–6 are discussed.

Three limonoids, trichiconin A (1) possessing a new carbon skeleton of a rearranged A,B-ring system and trichiconins B (2) and C (3) featuring an unprecedented A,B,D-seco skeleton, were isolated from the twigs of Trichilia connaroides. The carbon scaffold of trichiconin A is designated as trichiconane. Their structures with absolute stereochemistry were determined by spectroscopic data, X-ray crystallography, and CD analysis. Compounds 2 and 3 showed modest anti-HIV activities.

Eighteen new diterpenoids, named eurifoloids A–R (1–18), including ingenane (1 and 2), abietane (3–7), isopimarane (8–12), and ent-atisane (13–18) types, along with four known analogues were isolated from Euphorbia neriifolia. Eurifoloid M (13) represents a rare class of ent-atisane-type norditerpenoid. Eurifoloids E (5) and F (6) exhibited significant anti-HIV activities, with EC50 values of 3.58 ± 0.31 (SI = 8.6) and 7.40 ± 0.94 μM (SI = 10.3), respectively.

Fourteen new diterpenoids including clerodane (1–12), labdane (13), and norlabdane (14) types, as well as nine known analogues were isolated from the aerial parts of Croton laui. Their structures were established on the basis of spectroscopic analysis, and that of crotonolide H (11) was confirmed by single-crystal X-ray crystallography. Crotonolide A (1) exhibited moderate cytotoxicity against two tumor cell lines, HL-60 (human premyelocytic leukemia, IC50 9.42 μM) and P-388 (murine leukemia, IC50 7.45 μM), and crotonolide G (10) displayed significant antibacterial activity against a panel of Gram-positive bacteria.

An exploration for 11β-HSD1 inhibitors from Homonoia riparia returned eight new dammarane-type triterpenoids, horipenoids A–H (1–8), and a known oleanane-type triterpenoid (9). Their structures were elucidated on the basis of comprehensive analysis of spectroscopic data, and the absolute configuration of horipenoid E (5) was established by single crystal X-ray crystallography. Compounds 1–4 represent a rare class of octanortriterpenoids. Horipenoids C (3) and E (5) showed potent inhibition against mouse 11β-HSD1 with IC50 values of 0.810 ± 0.058 and 0.898 ± 0.215 μM, respectively.

Chemical investigation on Chukrasia tabularis var. velutina led to the identification of eight new phragmalin-type limonoids (1–8), as well as 20 known analogues. Compounds 1–4 are a rare class of C-15-acyl phragmalin-type limonoids, and particularly compounds 2–4 also possess a δ-lactone ring formed between C-16 and C-30. All the isolates were evaluated for inhibitory effects on NF-κB production, and four of which showed significant inhibitions.

Chemical investigation into the minor constituents of Aphanamixis grandifolia yielded three new diterpenoid dimers, aphadilactones E–G (1–3) featuring a new carbon skeleton. Their structures and absolute configurations were fully established by comprehensive spectroscopic data analysis and ECD calculation. Discovery of another two new dimers (4 and 5) suggested the structure of recently reported aphanamene A to be re-investigated. Compounds 1–5 showed moderate antimalarial activities with low micromolar IC50 values.

An exploration for 11β-HSD1 inhibitors from Homonoia riparia returned eight new dammarane-type triterpenoids, horipenoids A–H (1–8), and a known oleanane-type triterpenoid (9). Their structures were elucidated on the basis of comprehensive analysis of spectroscopic data, and the absolute configuration of horipenoid E (5) was established by single crystal X-ray crystallography. Compounds 1–4 represent a rare class of octanortriterpenoids. Horipenoids C (3) and E (5) showed potent inhibition against mouse 11β-HSD1 with IC50 values of 0.810 ± 0.058 and 0.898 ± 0.215 μM, respectively.

The plants of the Trigonostemon genus (Euphorbiaceae family) comprising about 50 species are mainly distributed in tropical and subtropical Asia. Chemical studies on this plant genus have led to the discovery of about 200 structurally diverse compounds in the last two decades, some of which have shown promising biological activities. Diterpenoids and alkaloids are the major and most important components of Trigonostemon plants, and are also the hot topics in synthetic chemistry. This review was attempted to provide the timely and comprehensive coverage of the chemical and biological studies on Trigonostemon plants, and especially to focus on the recent research progress.