Cephalotane diterpenoids: structural diversity, biological activity, biosynthetic proposal, and chemical synthesis.

Covering: up to the end of 2023Cephalotane diterpenoids are a unique class of natural products exclusive to the genus Cephalotaxus, featuring a rigid 7,6,5,6-fused tetracyclic architecture. The study of cephalotanes dates back to the 1970s, when harringtonolide (1), a Cephalotaxus troponoid with a peculiar norditerpenoid carbon skeleton, was first discovered. In recent years, prototype C20 diterpenoids proposed as cephalotane were disclosed, which triggered intense studies on this diterpenoid family. To date, a cumulative total of 105 cephalotane diterpenoids with great structural diversity and biological importance have been isolated. In addition, significant advances have been made in the field of total synthesis and biosynthesis of cephalotanes in recent years. This review provides a complete overview of the chemical structures, bioactivities, biosynthetic aspects, and completed total synthesis of all the isolated cephalotane diterpenoids, which will help guide future research on this class of compounds.

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Crotonoids A-H, Labdane-Type Diterpenoids with Anti-Inflammatory Activity from Croton sublyratus.

Croton sublyratus (Euphorbiaceae) is a traditional medicinal plant used by the Thai populace to treat helminthic infections and dermatologic conditions. In present study, eight new labdane-type diterpenoids, crotonoids A-H (1-8) and one known analogue (9) were isolated from the aerial parts of C. sublyratus. Compounds 6 and 7 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compound 8 exhibited a rare 14,15,17-trinor-labdane skeleton. The structures of all these diterpenoids were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 9 exhibited moderate anti-inflammatory activity via the inhibition of NO production in lipopolysaccharide-induced RAW 264.7 cells.

Highly Modified Sesquiterpene Lactones with Cytotoxic Activities from Strobocalyx chunii.

Three new germacranolide sesquiterpene lactones (SLs), strochunolides A-C (1-3, respectively), and a new guaianolide SL, strochunolide D (4), were isolated from Strobocalyx chunii and structurally characterized. Compound 1 is the first example of a dihomo-germacranolide SL, characterized by an unprecedented 6/10/5 tricyclic scaffold incorporating an additional fused δ-lactone C-ring. The structure of a known germacranolide SL, spicatolide C (5), was revised as its 8-epimer. Compound 3 exhibited potent in vitro cytotoxic activity against the HL-60 cell line, with an IC50 value of 0.18 ± 0.01 µM.

Sumatranins A-J: Lignans with Immunosuppressive Activity from Cleistanthus sumatranus.

Chemical investigation of the twigs of Cleistanthus sumatranus (Phyllanthaceae) led to the isolation of 10 undescribed lignans, sumatranins A-J (1-10). Compounds 1-4 are unprecedented furopyran lignans characterized by a unique 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene heterotricyclic framework. Compounds 9 and 10 are rare 9'-nor-dibenzylbutane lignans. Structures were established based on analyses of spectroscopic data, X-ray crystallographic data, and experimental ECD spectra. Immunosuppressive assays revealed compounds 3 and 9 displayed moderate inhibitory effects with good selectivity indexes against LPS-induced B lymphocyte proliferation.

Cephalotane-type C20 diterpenoids from Cephalotaxus fortunei var. alpina.

Seventeen new cephalotane-type diterpenoids, fortalides A-Q (1-17), along with five known analogues, were isolated from the seeds of Cephalotaxus fortunei var. alpina. Their structures were determined by extensive spectroscopic methods, as well as electronic circular dichroism (ECD) and X-ray crystallographic data analyses. Some isolates exhibited unusual structural features that were first found in cephalotane-type diterpenoids, such as the occurrence of the 7-oxabicyclo[4.1.1]octane moiety in 14 and 15 and the cis-arrangement of 3-OH and Me-19 in 9. Besides, the antiplasmodial activity of these compounds was evaluated in this study.

Multispecies comparative analysis reveals transcriptional specificity during Mongolian horse testicular development.

Mongolian horses have been bred and used for labor and transport for centuries. Nevertheless, traits of testicular development in Mongolian horses have rarely been studied; particularly, studies regarding the transcriptional regulation characteristics of testicular development are lacking. In this paper, transcription specificity during testicular development in Mongolian horses is highlighted via a multispecies comparative analysis and weighted gene co-expression network analysis (WGCNA). Interestingly, the results showed that most genes were up-regulated in the testes after sexual maturity, which is a phenomenon conserved across species. Moreover, we observed nine key genes involved in regulating Mongolian horse testicular development. Notably, unique transcription signatures of testicular development in Mongolian horses are emphasized, which provides a novel insight into the mechanistic study of their testicular development.

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.

Marinobacter vulgaris sp. nov., a moderately halophilic bacterium isolated from a marine solar saltern.

A facultatively anaerobic, Gram-stain-negative and non-gliding bacterium, designated F01T, was isolated from marine solar saltern in Weihai, PR China. Cells of F01T were 0.2-0.4 µm wide and 1.4-4.1 µm long, weakly catalase-positive and oxidase-negative. Growth of F01T was determined to occur at 4-40 °C (optimum, 33-37 °C), pH 6.5-8.5 (optimum, 7.0-8.0), and with 0.5-18.0 % (w/v) NaCl (optimum, 3.0-6.0 %). The 16S rRNA gene sequence analysis indicated that F01T represented a member of the genus Marinobacter within the family Alteromonadaceae. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate was most closely related to Marinobacter algicola DSM 16394T, with a sequence similarity of 97.5 %. The DNA G+C content of the isolate was 57.6 mol%. The major respiratory quinone of F01T was ubiquinone-9 (Q-9) and the major fatty acids were anteiso-C15 : 0, C16 : 0 and C18 : 1ω9c. The major polar lipids were phosphoaminolipid, phosphatidylglycerol and phosphatidylethanolamine. On the basis of the results of the phylogenetic analysis and phenotypic properties, it is concluded that F01T can be considered to represent a novel species in the genus Marinobacter, for which the name Marinobacter vulgaris sp. nov. is proposed. The type strain is F01T (=MCCC 1H00290T=KCTC 52700T).

Dysoxylactam A: A Macrocyclolipopeptide Reverses P-Glycoprotein-Mediated Multidrug Resistance in Cancer Cells.

A 17-membered macrocyclolipopeptide, named dysoxylactam A (1) comprising an unprecedented branched C19 fatty acid and an l-valine, was isolated from the plants of Dysoxylum hongkongense. The challenging relative configuration of 1 was established by means of residual dipolar coupling-based NMR analysis. The absolute configuration of 1 was determined by single-crystal X-ray diffraction on its p-bromobenzoate derivative (2). Compound 1 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 28.4 to 1039.7 at the noncytotoxic concentration of 10 µM. The mode-of-action study of 1 revealed that it inhibited the function of P-glycoprotein (P-gp), a key mediator in multidrug resistance.

Motilimonas pumila sp. nov., isolated from the gut of sea cucumber Apostichopus japonicus.

A facultatively anaerobic and Gram-negative bacterium, designated strain PLHSC7-2T, was isolated from the gut of sea cucumber Apostichopusjaponicus that had been collected from the coastal area of Yantai, China. The cells were rod-shaped and motile by means of polar flagella. The novel isolate grew optimally at 28-30 °C, in the presence of 2.0-3.0 % (w/v) NaCl and at pH 7.0-7.5. The sole respiratory quinone was Q-8 and the major fatty acids were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 0 and C17 : 0. The predominant polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain PLHSC7-2T was phylogenetically affiliated with the genus Motilimonas, and exhibited sequence similarity of 96.2 % toMotilimonas eburnea YH6T. The DNA G+C content was 45.5 mol%. On the basis of phenotypic , phylogenetic and genetic distinctiveness, strain PLHSC7-2T (=MCCC 1K03522T=KCTC 62589T) was classified as a novel species within the genus Motilimonas, for which the name Motilimonas pumila sp. nov. is proposed.

Cytotoxic Tigliane Diterpenoids from Croton damayeshu.

Chemical investigation of an EtOH extract of the twigs and leaves of Croton damayeshu afforded 10 new tigliane diterpenoids, crodamoids A-J (1-10), along with five known compounds. Their structures were elucidated by physical data analysis. Compounds 8, 9, and 15 displayed cytotoxic effects against two human tumor cell lines, A549 and HL-60 (IC50: 0.9-2.4 µM).

Structural Elucidation and Bioinspired Total Syntheses of Ascorbylated Diterpenoid Hongkonoids A-D.

Hongkonoids A-D (1-4), the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused tricyclic spiroketal butyrolactone moiety and diterpenoid-derived long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of spectroscopic data, chemical degradation, X-ray crystallography, CD analysis, and total synthesis. The total syntheses of compounds 1-4 were effectively accomplished by a convergent strategy with the longest linear sequences of 12-14 steps and overall yields of 5.4-9.6%. Notably, we exploited a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving the cascade reactions of an elaborate Claisen rearrangement, deprotections, and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework of 1-4. Some of the hongkonoids and/or synthetic analogs showed significant to moderate inhibitory activities against NF-κB, 11ß-HSD1, and sterol synthesis. The most active NF-κB inhibitor 34 exhibited distinct inhibition on the LPS-induced inflammatory responses in RAW 246.7 and primary BMDM cells.

Hanstruepera crassostreae sp. nov., a novel marine bacterium of the family Flavobacteriaceae isolated from an oyster.

A Gram-stain-negative, rod-shaped, non-motile, aerobic and orange-pigmented marine bacterium, designated strain L53T, was isolated from an oyster sample collected from the coast of Weihai, China (122.0° E 37.5° N). Growth of strain L53T occurred at 4-40 °C (optimum, 33 °C), at pH 6.5-8.0 (optimum, pH 7.5) and with 1.0-7.0 % (w/v) NaCl (optimum, 3.0 %). Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain L53T was closely related to Bizionia echini KCTC 22015T (96.9 %) and Hanstruepera neustonica JCM 19743T (96.1 %). Strain L53T was located in a distinct phyletic lineage in a discrete clade associated with H. neustonica JCM 19743T. The DNA G+C content of strain L53T was 33.5 mol%. The sole menaquinone was MK-6. The polar lipids comprised one phosphatidylethanolamine, four unidentified aminolipids and four unidentified lipids. The major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 0 G. Based on morphological, physiological and molecular properties as well as on phylogenetic distinctiveness, strain L53T should be placed in the genus Hanstruepera as representing a novel species, for which the name Hanstruepera crassostreae sp. nov. is proposed. The type strain is L53T (=KCTC 62247T=MCCC 1H00246T).

Quorumolides A-C, Three Cembranoids from Euphorbia antiquorum.

Three highly modified cembranoids, quorumolides A-C (1-3), were isolated from Euphorbia antiquorum. Compound 1 is the first example of a cembranoid embedding an α,ß-unsaturated-γ-lactone and a tetrahydro-2H-pyran motif within the 14-membered ring. Biosynthetically, it is particularly noteworthy that the stereochemistries of C-2 and C-12 in the pyran ring of 1-3 were opposite to those of marine-derived rare cembranoids.

Halofilum ochraceum gen. nov., sp. nov., a gammaproteobacterium isolated from a marine solar saltern.

A Gram-stain-negative, oxidase-negative, catalase-positive, facultative anaerobe, designated XJ16T, was isolated from a marine solar saltern on the coast of Weihai, China. Cells of strain XJ16T were long and rod-shaped. The colonies were ochre in colour and were able to reduce nitrate to nitrite. Optimal growth occurred at 33-37 °C (range, 20-45 °C) and in the presence of 8-10 % (w/v) NaCl (range, 2-20 %). The pH range for growth was found to be 6.5-9.5, with optimum growth at pH 7.5-8.0. Phylogenetic analysis based on the 16S rRNA gene sequence demonstrated that strain XJ16T was related to the phylum Proteobacteria. The most closely related neighbours were species of the genus Thioalkalivibrio, and the 16S rRNA gene sequence of strain XJ16T shared 93.1 % similarity with that of Thioalkalivibrio sulfidiphilus HL-EbGr7T and 93.0 % similarity with that of Thioalkalivibrio denitrificans ALJDT. The G+C content of the genomic DNA was 65.9 mol% (HPLC). The sole respiratory quinone was Q-8, and the predominant cellular fatty acids (>10 %) were iso-C15 : 0 2-OH/C16 : 1ω7c, C18 : 0 and C16 : 0 10-CH3. The predominant polar lipids in strain XJ16T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. Based on these phylogenetic, physiological and biochemical characteristics, strain XJ16T should be classified representing a novel species of a new genus within the family Ectothiorhodospiraceae, for which the name Halofilum ochraceum gen. nov., sp. nov. is proposed. The type strain of the type species is XJ16T (=KCTC 42259T=MCCC 1H00120T=CICC 23817T).

Algoriphagus resistens sp. nov., isolated from marine sediment.

Strain NH1T, a pink-pigmented, facultatively anaerobic, heterotrophic, catalase-positive and oxidase-negative, Gram-stain-negative marine bacterium, was isolated from marine sediment on the coast of Weihai, China. Cells of strain NH1T were rod-shaped, 0.8-2.0 µm in length and 0.5-1.0 µm in width. The strain was able to grow at 13-37 °C, pH 5.5-8.5, in the presence of 0.0-8.0 % (w/v) NaCl. Optimal growth was observed at 28 °C, with 3.0 % (w/v) NaCl and pH 6.5-7.0. Nitrate was reduced. The G+C content of the DNA was 41.9 mol%. The major isoprenoid quinone was MK-7 and the main cellular fatty acids (>10 %) were summed feature 3 (33.6 %) comprising iso-C15 : 0 2-OH and/or C16 : 1ω7c, and iso-C15:0 (19.2%). The major polar lipids in strain NH1T were phosphatidylethanolamine, unidentified lipids, phospholipid and aminolipids. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain NH1T was highly related to the type strains of Algoriphagus antarcticus (97.87 % 16SrRNA gene sequence similarity) and Algoriphagus ratkowskyi (97.56 %). On basis of the phenotypic and phylogenetic data, strain NH1T should be classified as representing a novel species of the genus Algoriphagus, for which the name Algoriphagus resistens sp. nov. is proposed. The type strain is NH1T (=MCCC 1H00140T=KCTC 52228T).

Labilibacter aurantiacus gen. nov., sp. nov., isolated from sea squirt (Styela clava) and reclassification of Saccharicrinis marinus as Labilibacter marinus comb. nov.

A Gram-stain-negative, facultatively anaerobic, orange-pigmented bacterium, designated HQYD1T, was isolated from a sea squirt (Styelaclava) and characterized using a polyphasic approach. Morphologically, strain HQYD1T exhibited rods with gliding motility. This novel isolate grew optimally at 28 °C in the presence of 2-3 % (w/v) NaCl. The 16S rRNA gene sequence was most similar to [Saccharicrinis] marinus Y11T (96.3 %), followed by Saccharicinis fermentans DSM 9555T (93.8 %). The dominant fatty acids of strain HQYD1T were identified as C16 : 0, C18 : 0 and iso-C15 : 0. Major polar lipids included an unidentified lipid and a phospholipid. The major respiratory quinone was found to be MK-7, and the genomic DNA G+C content was determined to be 35.1 mol%. Based on evidence from this taxonomic study, a novel genus, Labilibacter gen. nov., is proposed in the family Marinilabiliaceae with type species Labilibacter aurantiacus sp. nov. The type strain of the type species is HQYD1T (=MCCC 1K02304T=KCTC 42583T). As [Saccharicrinis] marinus Y11T clustered phylogenetically with strain HQYD1T, we also propose [Saccharicrinis] marinus Y11T be reclassified as Labilibacter marinus comb. nov. (type strain Y11T=CICC 10837T=KCTC 42400T).

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.

Woeseia oceani gen. nov., sp. nov., a chemoheterotrophic member of the order Chromatiales, and proposal of Woeseiaceae fam. nov.

A novel Gram-stain-negative, rods or bent rods, facultatively anaerobic, oxidase-negative and catalase-positive bacterium, designated XK5T, was isolated from coastal sediment from Xiaoshi Island, Weihai, China. Optimal growth occurred at 28-35 °C (range 8-42 °C) and pH 7.0-8.0 (range pH 6.0-9.0) with 1-3 % (w/v) NaCl (range 0.5-8 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain XK5T was 92.1 % similar to the type strain of Thioalkalivibrio thiocyanodenitrificans, 91.9 % to the type strain of Thioalkalivibrio sulfidiphilus and 91.8 % to the type strain of Thioalkalivibrio denitrificans; similarity to other species was less than 91 %. The isolate and closely related environmental clones formed a novel family level clade in the order Chromatiales. The polar lipid profile of the novel isolate consisted of phosphatidylethanolamine, phosphatidylglycerol and some other unknown phospholipids, aminolipids and lipids. Major cellular fatty acids were iso-C17 : 1ω9c and iso-C15 : 0 and the main respiratory lipoquinone was Q-8. The DNA G+C content of strain XK5T was 59.3 mol%. Comparative analysis of 16S rRNA gene sequences and characterization indicated that strain XK5T represents a novel species of a new genus within a novel family of the order Chromatiales, for which the name Woeseia oceani gen. nov., sp. nov. is proposed. The type strain of Woeseia oceani is XK5T ( = ATCC BAA-2615T = CICC 10905T). In addition, a novel family name, Woeseiaceae fam. nov., is proposed to accommodate the genus Woeseia.