Unprecedented Skeleton Research Articles

Herpetosin A, a nor-cucurbitane triterpenoid with a 5/6/6/5 ring system from Herpetospermum pedunculosum.

Two previously undescribed triterpenoids, herpetosin A (1) and herpetosin B (2), together with two known compounds, cucurbitacin B (3) and dihydrocucurbitacin E (4), were isolated from the seeds of Herpetospermum pedunculosum. Their structures were elucidated by analysis of the NMR, HR-ESI-MS, X-ray data and quantum chemical calculation. Compound 1 featured an unprecedented nor-cucurbitane triterpenoid skeleton with a 5/6/6/5 ring system. Among all the isolates, compound 4 exhibited anti-proliferative effect with IC50 values of 4.5 ± 0.1 μM against A549 cells, 8.2 ± 0.5 μM against MDA-MB-231 cells, and 2.4 ± 0.3 μM against HepG2 cells, respectively.

Glasesterterpenoids A−C: three sesterterpenoids with 7-cyclohexyldecahydronaphthalene carbon skeleton isolated from the root of Lindera glauca

Three novel sesterterpenoids glasesterterpenoids A−C (1−3), featuring an unprecedented 7-cyclohexyldecahydronaphthalene carbon skeleton, were isolated from the root of Lindera glauca (L. glauca). Their structures were elucidated by quantum chemical calculations and spectroscopic methods. The biogenetic pathway for 1−3 is proposed. In the bioassay, glasesterterpenoid C exhibited DNA topoisomerase 1 (Top1) inhibitory activity compared with the positive control, camptothecin. These findings represent the first examples of sesterterpenoids with a 7-cyclohexyldecahydronaphthalene carbon skeleton from the root of L. glauca.

Kopsileuconines A−D: Bisindole alkaloids with cytotoxic activity from Kopsia hainanensis

Kopsileuconines A−D (1−4), four monoterpenoid bisindole alkaloids with unprecedented skeletons, along with their biosynthetically related precursors (5−8) were isolated from the roots of Kopsia hainanensis. Compound 1 possessed an undescribed C-6−C-5′ dimerization pattern of aspidofractinine-type alkaloids. Compounds 2−4 were rhazinilam-kopsine (2) and rhazinilam-aspidofractinine type (3 and 4) bisindole alkaloids with undescribed skeletons, respectively. Their structures with absolute configurations were fully accomplished by extensive spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A plausible biosynthetic pathway for 1−4 was proposed. Compound 2 exhibited a significant inhibitory effect against human lung cancer cell lines PC9 (EGFR mutant), with an IC50 value of 15.07 ± 1.19 μM.

A polysubstituted cyclopentane and two glycerol esters from the engineered strain Streptomyces sp. S35-LAL1

Activation of silencing gene clusters is an important way to discover structurally novel compounds. In this study, three undescribed compounds were obtained from an engineered strain of Streptomyces sp. S35-LAL1. They include a polysubstituted cyclopentane with an unprecedented 10-carbon skeleton (1) and two glycerol esters (2 and 3). The structures of compounds 1–3 were elucidated through analysis of their spectroscopic data including 1D, 2D NMR, optical rotation, and electronic circular dichroism (ECD).

Ganopyrone A, a highly rearranged lanostane triterpenoid with antimalarial activity from artificially cultivated fruiting bodies of Ganoderma colossus

Three previously undescribed highly modified lanostane triterpenoids, ganopyrone A, ganocolossusin I, and ganodermalactone Y, were isolated from the artificially cultivated fruiting bodies of the basidiomycete Ganoderma colossus TBRC-BCC 17711. Ganopyrone A possesses an unprecedented polycyclic carbon skeleton with an α-pyrone ring and C-18/C-23 bond. It showed antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with an IC50 value of 7.8 μM (positive control: dihydroartemisinin, IC50 1.4 nM), while its cytotoxicity (Vero cells) was much weaker (IC50 103 μM).

Synthesis of Bridged Bicyclic Systems peri‐Annulated to the Indole Ring: Tropane‐Fused Indoles

AbstractYtterbium triflate catalysed domino reaction of (3‐formyl‐4‐indolyl)‐derived donor‐acceptor cyclopropane with primary amines provides a simple approach to an unprecedented tetracyclic skeleton in which tropane system is peri‐annulated with an indole core. This process involves the formation of an imine and its (3+2)‐cross‐cycloaddition with donor‐acceptor cyclopropane moiety, yielding tropane‐fused indole core under mild reaction conditions. These products are of significant interest for pharmacology as potential hybrid molecules with a dual mode of action.

Taxodin A, a Cytotoxic C30 Terpenoid from Taxodium mucronatum with a Unique Skeleton.

Taxodin A (1), a unique C30 terpenoid featuring an unprecedented skeleton composed of an abietane-type diterpene and a menthane-type monoterpene, was obtained from the leaves and branches of Taxodium mucronatum. The structure and absolute configuration of compound 1 was unequivocally established by the combination of extensive spectroscopic analyses and X-ray single-crystal diffraction analysis. Compound 1 exhibited potent cytotoxic activities against A549, SMMC-7721, MDA-MB-231, and SW480 cell lines with IC50 values of 15.35±0.73, 8.49±0.35, 17.53±0.79, 18.93±0.60 μM, respectively.

Pullenvalenes A-D: Nitric Oxide-Mediated Transcriptional Activation (NOMETA) Enables Discovery of Triterpene Aminoglycosides from Australian Termite Nest-Derived Fungi.

We report on the use of nitric oxide-mediated transcriptional activation (NOMETA) as an innovative means to detect and access new classes of microbial natural products encoded within silent biosynthetic gene clusters. A small library of termite nest- and mangrove-derived fungi and actinomyces was subjected to cultivation profiling using a miniaturized 24-well format approach (MATRIX) in the presence and absence of nitric oxide, with the resulting metabolomes subjected to comparative chemical analysis using UPLC-DAD and GNPS molecular networking. This strategy prompted study of Talaromyces sp. CMB-TN6F and Coccidiodes sp. CMB-TN39F, leading to discovery of the triterpene glycoside pullenvalenes A-D (1-4), featuring an unprecedented triterpene carbon skeleton and rare 6-O-methyl-N-acetyl-d-glucosaminyl glycoside residues. Structure elucidation of 1-4 was achieved by a combination of detailed spectroscopic analysis, chemical degradation, derivatization and synthesis, and biosynthetic considerations.

Microascones, Decahydrofluorene-Class Alkaloids from the Marine-Derived Fungus Microascus sp. SCSIO 41821.

Eight new decahydrofluorene-class alkaloids, microascones A and B (1 and 2), 2,3-epoxyphomapyrrolidone C (3), 14,16-epiascomylactam B (4), 24-hydroxyphomapyrrolidone A (5), and microascones C-E (6-8), along with five known analogs (9-13) were isolated from the marine-derived fungus Microascus sp. SCSIO 41821. Compounds 1 and 2 have an unprecedented complex macrocyclic alkaloid skeleton with a 6/5/6/5/6/5/13 polycyclic system. Their structures and absolute configurations were determined by spectroscopic analysis, quantum chemical calculations of ECD spectra, and 13C NMR chemical shifts. Compounds 10-13 showed selective enzyme inhibitory activity against PTPSig, PTP1B, and CDC25B, and 4, 9, and 10 exhibited strong antibacterial activity against seven tested pathogens. Their structure-bioactivity relationship was discussed, and a plausible biosynthetic pathway for 1-8 was also proposed.

Highly modified cephalotane-type diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A–F (1–6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.

Koningipyridines A and B, two nitrogen-containing polyketides from the fungus Trichoderma koningiopsis SC-5

Two novel koninginin derivatives, koningipyridines A and B (1 and 2), along with four known compounds (3˗6) were isolated from the EtOAc extract of the endophytic fungus Trichoderma koningiopsis SC-5. Among them, koningipyridine A featured an unprecedented pentacyclic ketal skeleton with the formation of a fascinating 6/6/5/6/5 fused ring system and shared a characteristic pyridine core, which represents the first example of nitrogen-containing koninginin-type natural product. Moreover, koningipyridine B was the first member in the koninginin family sharing a unique 6/6/5 dihydropyridine skeleton, and it was suggested to be the critical biosynthetic precursor of koningipyridine A. The structures of 1 and 2 were elucidated by the interpretation of 1D and 2D NMR spectroscopy, HRESIMS data, as well as theoretical calculations of 13C NMR and electronic circular dichroism (ECD). Moreover, all isolates were screened for antimicrobial activities against Staphylococcus aureus, MRSA, and Escherichia coli as well as the cytotoxic effects against three cancer cell lines (A549, Hela, and HepG2).Graphical

Overview of the chemistry and biological activities of natural atisine-type diterpenoid alkaloids.

Atisine-type C20-diterpenoid alkaloids (DAs) are a very important class of diterpenoid alkaloids, which play an important role in the biosynthesis of DAs. To date, 87 atisine-type DAs and 11 bis-DAs containing an atisine unit have been reported from five genera in two families. The genus Spiraea in Rosaceae family could be regarded as the richest resource for atisine-type DAs, followed by the genera Delphinium and Aconitum in the Ranunculaceae family. Among the reported atisine-type DAs, several possess unprecedented skeletons. Natural atisine-type DAs have a wide range of biological activities, including antitumor, antiplatelet aggregation, biological control, and anti-inflammatory, analgesic, antiarrhythmic, and cholinesterase inhibitory effects, which are closely related to their structures. In particular, the antiparasitic effect of atisine-type DAs is more prominent than that of other types of DAs, which highlights their potential in antiparasite drug discovery. In summary, the high chemical and biological diversity of atisine-type DAs indicates their great potential as a vast resource for drug discovery.

Lignan and Phthalide Derivatives from the Rhizome of Ligusticum chuanxiong (Rhizoma chuanxiong) and Evaluation of Their anti-Xanthine Oxidase Activities.

The previous research results showed that the extracts of ethyl acetate of the rhizome of Ligusticum chuanxiong (Rhizoma chuanxiong) possessed significant antigout effects in model mice. To explore the active ingredients responsible for the effects, phytochemical studies were performed, which led to the isolation of three rare 8', 9-linked neolignans, ligusticumins A-C (1-3), together with two novel phthalide-phenylpropanoid heterodimers, ligusticumalides A-B (4 and 5). It is noteworthy that 4 possesses an unprecedented 7-styryl phthalide skeleton. The structures and absolute configurations of 1-5 were elucidated by one-dimensional (1D) and two-dimensional (2D) NMR spectroscopy and electron-capture detector (ECD) spectroscopic methods. The bioassay results showed that compounds 1, 2, 3, and 5 presented moderate inhibitory activities against xanthine oxidase (XO) and 4 possessed a significant XO inhibitory effect with an IC50 value of 93.88 μM. This is the first time to investigate the anti-XO active ingredients of R. chuanxiong, which provides valuable information for searching for new antigout agents from natural products.

Pogocablanols A–G, a new class of sesquiterpenoids with an unprecedented bicyclic sesquiterpenoid skeleton from Pogostemon cablin (patchouli) and their activities

Pogocablanols A–G (1–7), seven new compounds with an unprecedented sesquiterpenoid skeleton, were isolated from the aerial parts of Pogostemon cablin. This novel type of sesquiterpenoids, named pogocablane-type sesquiterpenoids, possesses a bicyclic nonisoprenoid system, including a five-membered carbocycle with a methyl group, a six-membered carbocycle with two methyl groups, and a methylene connecting the two carbocycles. Particularly, three isomers have an interesting 1-oxaspiro[4,4]nonane moiety. Their structures and absolute configurations were determined using extensive spectroscopic evidence, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Pogocablanols A–D (1–4) exhibited a concentration-dependent inhibitory effect on rat jejunum smooth muscle contraction induced by acetylcholine, with Emax values varying from 48.87 ± 4.01% to 69.02 ± 7.54%. Preliminary structure–activity relationship analysis suggested that the oxaspirocycle and the pyran ring in pogocablanols are important structural features for the relaxing effects on jejunum smooth muscle. This study offered crucial support for more investigation and development of P. cablin by showing that these pogocablane-type sesquiterpenoids had the potential to be applied in pharmaceutical and functional food formulations.

Phomaketals A and B, pentacyclic meroterpenoids from a eupC overexpressed mutant strain of Phoma sp.

Phomaketals A (1) and B (2), two tropolonic meroterpenoids with the unprecedented pentacyclic skeletons, were isolated from the solid-substrate fermentation cultures of a eupC overexpressed mutant strain of the fungus Phoma sp., together with a biogenetically related secondary metabolite pughiinin B (3), and the known one noreupenifeldin B (4). The structures of 1–3 were elucidated primarily by nuclear magnetic resonance (NMR) experiments. The absolute configurations of 1 and 2 were assigned by electronic circular dichroism calculations and the calculated NMR with DP4+ analysis, while that of 3 was established by single-crystal X-ray diffraction analysis using Cu Kα radiation. Biogenetically, phomaketals A (1) and B (2) could be derived from the hypothetical tropolonic sesquiterpene intermediates neosetophomone B (6) and 9-R-neosetophomone B (6′), respectively, via different reactions cascades. Compound 1 showed antiproliferative effect only against the SUPB15 cells, with an 50% inhibitory concentration (IC50) value of 4.85 µmol/L, while the co-isolated known meroterpenoid 4 displayed potent effects against three tumor cell lines, SUPB15, EL4, and H9, showing IC50 values of 0.36–27.08 µmol/L.

Diphenyl Ether Derivative Rhexocerins and Rhexocercosporins from the Endophytic Fungus Rhexocercosporidium sp. Dzf14 Active against Gram-Positive Bacteria with Multidrug-Resistance.

Ten new diphenyl ether polyketides, including rhexocerins A-D (1-4) and rhexocercosporins A-F (5-10), together with three known congeners (11-13), were isolated from the endophytic fungus Rhexocercosporidium sp. Dzf14 obtained from Dioscorea zingiberensis. Their structures were elucidated by analysis of NMR and HRESIMS data, and their absolute configurations were determined by quantum chemical ECD calculations and X-ray crystallography. Compounds 1-4 featured an unprecedented tetracyclic carbon skeleton (6/7/5/6). Among them, compounds 1 and 5-9 showed antibacterial activities against methicillin-resistant S. aureus T144 and vancomycin-resistant E. faecalis 10.

Peniciriols A and B, two new citrinin derivatives from an endophytic fungus Penicillum citrinum TJNZ-27

Two undescribed citrinin derivatives, named peniciriols A-B (1–2), together with six known compounds were isolated from endophytic fungus Penicillum citrinum TJNZ-27. The structures of two new compounds were well established by the detail interpretation of NMR and HRESIMS data as well as ECD measurement powered by molecular calculation. Among them, compound 1 shared an unprecedented dimerized citrinin skeleton with the formation of an intriguing 9H-xanthene ring system, whereas compound 2 possess a highly substituted phenylacetic acid skeleton, which was rarely-occurring in natural secondary metabolites. Moreover, these novel compounds were tested for cytotoxic and antibacterial activities, whereas these novel compounds did not exhibit any noticeable cytotoxic or antibacterial activities.

Isolation and antihyperglycemic effects of garcibractinols A–H, intricate polycyclic polyprenylated acylphloroglucinols from the fruits of Garcinia bracteata

Eight previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from the fruits of Garcinia bracteata and named garcibractinols A–H. Garcibractinols A–F (compounds 1–6) were bicyclic polyprenylated acylphloroglucinols (BPAPs) sharing a rare bicyclo[4.3.1]decane core. On the other hand, garcibractinols G and H (compounds 7 and 8) shared an unprecedented BPAP skeleton bearing a 9-oxabicyclo[6.2.1]undecane core. The structures andabsolute configurations of compounds 1–8 were determined by spectroscopic analysis,single-crystal X-ray diffraction analysis, and quantum chemical calculation. The breakage of the C-3/C-4 linkage through the retro-Claisen reaction was a key step in the biosynthesis of compounds 7 and 8. The antihyperglycemic effects of the eight compounds were evaluated in insulin-resistant HepG2 cells. At a concentration of 10 μM, compounds 2 and 5–8 significantly increased the glucose consumption in the HepG2 cells. Furthermore, compound 7 was more effective than metformin (which was used as a positive control) in promoting glucose consumption in the cells. The findings of this study suggest that compounds 2 and 5–8 have anti-diabetic effects.

Analgesic sesquiterpenes from the roots of Rhododendron micranthum

Two new guaiane-derived sesquiterpenes, rhodomicranins A−B (1−2), four new cadinane-type sesquiterpenes, rhodomicranins C–F (3−6), one new eudesmane-type sesquiterpene, rhodomicranin G (7), and nine known analogues (8−16) were isolated from the roots of Rhododendron micranthum. Compound 1 represent an unprecedented B-norguaiane sesquiterpene carbon skeleton. The structures and absolute configurations of the new compounds were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. The plausible biosynthetic pathway for all compounds is proposed. Furthermore, the analgesic activities of compounds 1−16 were evaluated by an acetic acid-induced writhing test. At a dose of 1 mg/kg, compounds 2, 4−5, 9−10, 13, and 15 demonstrated significant analgesic effects with writhe inhibition rates ranging from 61.2% to 83.6%. In particular, compound 4 exhibited the highest potency of analgesic activity (1 mg/kg) with a writhe inhibition rate of 83.6%, equivalent to that produced by morphine at the same dose.

Influence of the Steric/Electronic Properties of N-Aryl Substituents in Cycloplatinated Guanidinate(1−) Complexes on the Formation of Discrete Pt → Ag Complexes and One-Dimensional Coordination Polymer

The reactions of cycloplatinated guanidinate(1-) complexes 1-6 with AgTFA (TFA = OC(O)CF3) in 1:1 and 1:2 PtII/AgI molar ratios afforded complexes containing three types of Pt2Ag2 skeletons (7-10, 11, and 13), one 1D CP containing Pt2Ag3 skeleton (16), and a Pt2Ag4 complex (17) in 91-95% (method 1), 73-82% (method 2) (7-10), and 54-79% (11, 13, 16, and 17) yields. The reactions of 11 with 2,6-XylNC (2,6-Xyl = 2,6-Me2C6H3) and 4-DMAP (4-dimethylaminopyridine) gave a neutral complex 18 and an ionic complex 19, respectively. Molecular structures of 12 complexes were unambiguously determined by single-crystal X-ray diffraction. Ten complexes contain unprecedented PtAg skeletons and are shown to contain multiple number of dative Pt → Ag bonds supported by the TFA ligand, platinated carbon of the TAG ligand, or both these ligands in conjunction with the Ag-Ag contacts stabilized by argentophilic interaction. Further, the new complexes were characterized by analytical, IR, and multinuclear NMR (19F, 1H, 13C{1H}, and 195Pt) spectroscopies, powder X-ray diffraction, and TGA/DTA. In solution, 9 and 19 exist in more than one form as identified by multinuclear NMR, and this behavior is ascribed to the restricted (N2)C-N(H)Ar single-bond rotation of the TAG ligand. The photophysical properties of 9 and 11 are reported.