Drymariamides A-J, Antiadipogenic Cyclopeptides Incorporating Noncanonical Amino Acids from Drymaria cordata.

Herein, we report an extensive phytochemical study on the whole plant of Drymaria cordata, which led to the isolation of ten new orbitides, named drymariamides A-J (1-10). Compounds 2, 3, and 5 incorporate rare residues of noncanonical amino acids of kynurenine (Kyn) or 3a-hydroxypyrroloindoline (HPI). Their structures with absolute configurations were elucidated by a combination of spectroscopic analysis, advanced Marfey's method, X-ray diffraction, and electronic circular dichroism analysis. Compounds 1-10 exhibited antiadipogenic effects in 3T3-L1 adipocytes, and the most potent compound 7 showed an EC50 value of 1.17 ± 0.19 µM.

Baccaramiones A-D, Four Highly Oxygenated and Rearranged Trinorditerpenoids from Baccaurea ramiflora.

Baccaramiones A-D (1-4), four highly oxygenated and rearranged trinorditerpenoids, were isolated from Baccaurea ramiflora. Compound 1 is a 1(10 → 5)-abeo-15,16,17-trinor-ent-abietane featuring a unique 5/6/6 spirocyclic scaffold, and 2-4 are the first example of a novel 20(10 → 5)-abeo-15,16,17-trinor-ent-abietane skeleton. Their structures were established by spectroscopic analysis, X-ray crystallography, and electronic circular dichroism calculations. A plausible biosynthetic pathway for 1-4 was proposed. Interestingly, compounds 3 and 4 exhibited significant immunosuppressive activities against concanavalin A-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation in vitro.

Densely Functionalized Macrocyclic Sesquiterpene Pyridine Alkaloids from Maytenus austroyunnanensis.

Eleven densely functionalized new dihydro-ß-agarofuran sesquiterpenoid derivatives, named maytenoids A-K (1-11), as well as one known analog, were isolated and characterized from Maytenus austroyunnanensis. Their structures were assigned based on analysis of spectroscopic data and X-ray crystallography. Compounds 1-9 are macrocyclic sesquiterpene pyridine alkaloids generated by the respective acylation of the hydroxy groups at C-3 and C-13 of dihydro-ß-agarofuran sesquiterpenoids via diverse pyridine dicarboxylic acids. Compounds 1, 2, 5-10, and 12 exhibited significant inhibitory effects on NO production at 10 µM in lipopolysaccharide (LPS)-stimulated BV2 cells.

Dolabrane-Type Diterpenoids with Immunosuppressive Activity from Koilodepas hainanense.

Thirteen new dolabrane-type diterpenoids, koilodenoids A-M (1-13), including a chlorinated congener (2), along with six known analogues, were isolated from Koilodepas hainanense. The structures were determined by analysis of spectroscopic data, ECD spectra, and X-ray crystallographic studies. The absolute configuration of C-15 in the 15,16-diol unit of compounds 4 and 5 was established by using the dimolybdenum tetraacetate [Mo2(AcO)4]-induced ECD method. Compounds 4, 7, 16, 17, and 19 showed moderate to significant immunosuppressive activities against the proliferation of T and B lymphocytes in vitro, with compound 16 being the most potent (IC50 0.86 and 0.29 µM, respectively).

Horienoids A and B, Two Heterocoupled Sesquiterpenoid Dimers from Hedyosmum orientale.

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

Sublyratins A-O, Labdane-Type Diterpenoids from Croton sublyratus.

Fifteen new labdane-type diterpenoids, sublyratins A-O (1-15), along with four known analogues (16-19) were isolated from the aerial parts of Croton sublyratus. Their structural assignments were challenging due to the stereoisomeric features evident and were achieved by analyzing comprehensively the spectroscopic data and electronic circular dichroism spectra and using X-ray crystallographic analysis. Compounds 9 and 16-18 displayed cytotoxic activity against the HL-60 cell line with IC50 values of 1.5-2.8 µM.

Cephalodiones A-D: Compound Characterization and Semisynthesis by [6+6] Cycloaddition.

Cephalodiones A-D (1-4), the first example of C19 -norditerpenoid dimers, were isolated and fully characterized from a Cephalotaxus plant. These new skeletal natural products shared a unique tricyclo[6.4.1.12,7 ]tetradeca-3,5,9,11-tetraene-13,14-dione core that was capped in both ends with rigid multicyclic ring systems either C2 -symmetrically or asymmetrically. Compounds 1-4 were proposed to be biosynthetically produced by the [6+6]-cycloaddition of two identical C19 -norditerpenoid troponoids, which was validated by the semisyntheses of dimers 2-4. Moreover, some compounds showed significant inhibition on Th17 cell differentiation.

Daphnillonins A and B: Alkaloids Representing Two Unknown Carbon Skeletons from Daphniphyllum longeracemosum.

Two highly rearranged daphniphyllum alkaloids, daphnillonins A (1) and B (2), were isolated from Daphniphyllum longeracemosum and structurally characterized by a combination of diverse methods, including the calculation of electronic circular dichroism. Compound 1 possesses an unprecedented carbon architecture with a very unique 8-methyl-6-azabicyclo[3.2.1]octane moiety, and compound 2 represents a new carbon skeleton with an uncommon 7/6/5/7/5/5-fused ring system. The biosynthetic pathways for the two alkaloids were proposed with the concurrent major alkaloids as the precursors.

Publisher Correction: Integrating yeast chemical genomics and mammalian cell pathway analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structural Elucidation and Total Synthesis of Three 9-Norlignans from Curculigo capitulata.

Capitulactones A-C, three unprecedented 9-norlignans featuring a unique 3,5-dihydrofuro[2,3- d]oxepin-7(2 H)-one scaffold, were isolated from the roots of Curculigo capitulata. Their structures with absolute configurations were unambiguously established by a combination of spectroscopic data, ECD analysis, and total synthesis. Biomimetic total syntheses of three pairs of the corresponding enantiomers were achieved in 9-10 steps with overall yields of 14.8, 12.7, and 10.3%, respectively. Notably, the unique scaffold of the common western hemisphere of the molecules was constructed by using the oxidation-reduction strategy from benzodihydrofuran.

Maximumins A-D, Rearranged Labdane-Type Diterpenoids with Four Different Carbon Skeletons from Amomum maximum.

Four highly rearranged labdane-type diterpenoids, maximumins A-D (1-4) possessing different new carbon skeletons, together with a biosynthetically related known analog 5 were isolated from Amomum maximum. The structures of new compounds with absolute configurations were characterized by spectroscopic and computational approaches. The plausible biogenetic pathways for 1-4 were proposed. These compounds showed moderate to weak activities against nuclear factor kappa B (NF-κB).

17- nor-Cephalotane-Type Diterpenoids from Cephalotaxus fortunei.

Seventeen new 17- nor-cephalotane-type diterpenoids, fortalpinoids A-Q (1-17), were isolated from the seeds of Cephalotaxus fortunei var. alpine. Compound 12 represents the first 17- nor-cephalotane-type diterpenoid featuring an 8-oxabicyclo[3.2.1]oct-2-ene moiety. The absolute configuration of fortunolide A (18) was determined for the first time, and the structure of cephinoid Q was revised to 14- epi-cephafortoid A (24) by X-ray crystallographic data analysis. Some of the compounds showed significant cytotoxicity against A549 and HL-60 cells, and the structure-activity relationship of this compound class is discussed.

Integrating yeast chemical genomics and mammalian cell pathway analysis.

Chemical genomics has been applied extensively to evaluate small molecules that modulate biological processes in Saccharomyces cerevisiae. Here, we use yeast as a surrogate system for studying compounds that are active against metazoan targets. Large-scale chemical-genetic profiling of thousands of synthetic and natural compounds from the Chinese National Compound Library identified those with high-confidence bioprocess target predictions. To discover compounds that have the potential to function like therapeutic agents with known targets, we also analyzed a reference library of approved drugs. Previously uncharacterized compounds with chemical-genetic profiles resembling existing drugs that modulate autophagy and Wnt/ß-catenin signal transduction were further examined in mammalian cells, and new modulators with specific modes of action were validated. This analysis exploits yeast as a general platform for predicting compound bioactivity in mammalian cells.

Cytotoxic 8,9-seco-ent-kaurane diterpenoids from Croton kongensis.

Chemical study on the ethanolic extract generated from the aerial parts of Croton kongensis led to the isolation of three new 8,9-seco-ent-kaurane diterpenoids, kongeniods A‒C (1‒3), together with seven known analogs (4-10). The structures of these compounds were assigned by spectroscopic data analysis. The vitro cytotoxic tests showed that compounds 1-3 exhibited strong activities against HL-60 cell lines with IC50 values of 0.47, 0.58, and 1.27 µM, respectively.

Six new diterpenoids from Croton laevigatus.

Six new ent-labdane-type diterpeniods (1‒6), along with one known compound, were identified from the twigs and leaves of Croton laevigatus. Their structures were elucidated on the basis of extensive spectroscopic interpretation. Compounds 2 and 7 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 4.11 and 8.33 µg/ml, respectively.

Cephanolides A-J, Cephalotane-Type Diterpenoids from Cephalotaxus sinensis.

Ten new cephalotane-type diterpenoids, cephanolides A-J (1-10), and two known analogues were isolated and characterized from Cephalotaxus sinensis. Compounds 1-3 represent the first examples of A-ring-contracted cephalotane-type dinorditerpenoids, and compound 4 is an A-ring-contracted norditerpenoid. The biosynthetic pathways for compounds 1-4 are postulated with the coexisting cephalotane-type troponoids as the precursors. Compounds 11 and 12 showed significant cytotoxicities against a panel of tumor cell lines (A549, KB, HL-60, and HT-29) with IC50 values ranging from 0.464 to 6.093 µM.

Diterpenoids and Lignans from Cephalotaxus fortunei.

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.

Cephalotanins A-D, Four Norditerpenoids Represent Three Highly Rigid Carbon Skeletons from Cephalotaxus sinensis.

Four polycyclic norditerpenoids, cephalotanins A-D (1-4) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis and structurally characterized by a combination of various methods. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Biosynthetic pathways for 1-4 were proposed by involving diverse and very fascinating chemical events with the coexisting cephalotane troponoids as the precursors. Compound 1 exhibited good NF-κB inhibition with an IC50 value of 4.12±0.61 µΜ.

Phainanoids A-F, a new class of potent immunosuppressive triterpenoids with an unprecedented carbon skeleton from Phyllanthus hainanensis.

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.

Unprecedented sesterterpenoids, orientanoids A-C: discovery, bioinspired total synthesis and antitumor immunity.

Sesterterpenoids are a very rare class of important natural products. Three new skeletal spiro sesterterpenoids, named orientanoids A-C (1-3), were isolated from Hedyosmum orientale. Their structures were determined by a combination of spectroscopic data, X-ray crystallography, and total synthesis. To obtain adequate materials for biological research, the bioinspired total syntheses of 1-3 were effectively achieved in 7-8 steps in overall yields of 2.3-6.4% from the commercially available santonin without using any protecting groups. In addition, this work also revised the stereochemistry of hedyosumins B (6) and C (10) as 11R-configuration. Tumor-associated macrophages (TAMs) have emerged as important therapeutic targets in cancer therapy. The in-depth biological evaluation revealed that these sesterterpenoids antagonized the protumoral and immunosuppressive functional phenotype of macrophages in vitro. Among them, the most potent and major compound 1 inhibited protumoral M2-like macrophages and activated cytotoxic CD8+ T cells, and consequently inhibited tumor growth in vivo.