3.6. Jatrophane
Jatrophane diterpenoids possess a bicyclo[10.3.0]pentadecane skeleton, and occur exclusively in the Euphorbiaceaefamily.[3, 122] Heliojatrones A and B (108 and 109 ), two jatrophane-derived diterpenoids with an unprecedented trans -bicyclo[8.3.0]tridecane core, have been isolated from the whole plants of Euphorbia helioscopia . 109 showed significant Pglycoprotein inhibitory activity. Euphopias A−C (110112 ), three rearranged jatrophane-type diterpenoids with unexpected carbon skeleton, have been isolated from Euphorbia helioscopia . 111 could ameliorate mitochondria damage, thereby interrupting NLRP3 inflammasome activation. Euphohelioscoids A (113 ) and B (114 ), diterpenoids with rearranged 9(10→11)-abeo -10,12-cyclojatrophane skeleton and the first (15S )‑jatrophane have been isolated fromEuphorbia helioscopia .[123] Yin’s group has studied Euphorbia plants a lot, and they have identified a serious of highly modified jatrophane diterpenoids, such as euphorhelipanes A (115 ) and B (116 ) from the whole plants of Euphorbia helioscopia ,[124]jatrofolianes A (117 ) and B (118 ) from Jatropha gossypiifolia ,[125] euphohyrisnoids A (119 ) and B (120 ) from the seeds of Euphorbia lathyris ,[7] and euphylonoids A (121 ) and B (122 ) from Euphorbia hylonoma .[126] 115 and 116showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells, and 122 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.
4. Sesterterpenoids
Sesterterpenoids are a small group of terpenoids containing 25 carbons, which are derived from the linear precursor GFPP. Sesterterpenoids have been isolated from many kinds of organisms such as plants, fungi, and marine sponge, with a great diversity of structures and skeletons and broad biological functions. A review has introduced the structures and bioactivities of marine sesterterpenoids since 2013 until 2017;[127] another review has summarized the distribution, chemistry, biological activities, biosynthesis and evolution of plant sesterterpenoids since 1969 until 2021.[128] In this contribution, some typical sesterterpenoids with unprecedented carbon skeletons will be introduced, including their chemical structures and biological activities.
Pre-leucosceptroid (123 ) and isopre-leucosceptroid (124 ) are intriguing monocarbocyclic sesterterpenoids.123 has been identified from the leaves of Leucosceptrum canum , while its isomer 124 has been isolated from the excrement of Nacna malachitis larvae, a specialist insect feeding on L. canum . Extensive spectroscopic analysis and quantum chemical calculations have confirmed their absolute configurations.[129]
A pair of enantiomeric bicyclic sesterterpenoids, (±)-hippolide J (125 and 126 ), have been isolated from the marine sponge Hippospongia lachne collected from the South China Sea.[130] Both of them showed potent antifungal activity against three strains of hospital-acquired pathogenic fungi,Candida albicans SC5314, Candida glabrata 537, andTrichophyton rubrum Cmccftla, with MIC50 values of 0.125−0.25 μ g/mL.[130]
Two unique tricyclic sesterterpenoids linderasesterterpenoids A (127 ) and B (128 ), with an unprecedented 7-cyclohexyldecahy-droazulene carbon skeleton, have been separated from the root of Lindera glauca .[131]127 and 128 showed good inhibitory activities against LPS-induced NO production in RAW 264.7 cells with IC50values of 18.9 and 16.2 μ M, respectively, as compared to the positive control (indomethacin, IC50 = 30.9μ M).[131] Gentianelloids A (129 ) and B (130 ), a pair of sesterterpenoid epimers, possessing an unusual 10,11-seco -gentianellane skeleton, have been obtained from the traditional Uighur medicine Gentianella turkestanorum . Their structures including absolute configurations have been determined by extensive spectroscopic and single-crystal X-ray diffraction analyses. Moreover, the plausible biosynthetic origins of their skeletons are both via the tetracyclic precursor nitidasin, which must be derived from GFPP via cyclization and oxidation reactions (Fig. 16).[132]
Eurysoloids A (131 ) and B (132 ), two novel diastereomeric sesterterpenoids possessing a pentacyclic 5/6/5/10/5 framework with an unusual macrocyclic ether system, have been reported from Eurysolen gracilis Prain, and their absolute configurations have been assigned by single-crystal X-ray diffraction and DP4+analyses.[133]Peniroquesines A−C (133135 ), possessing an 5/6/5/6/5 fused pentacyclic ring system, identified based on NMR spectroscopy, MS, Mosher’s method, and single-crystal X-ray crystallography, have been isolated from the fungus Penicillium roquefortiYJ-14.[134] Additionally, compounds 133and 134 showed a potent inhibitory effect on nitric oxide production in LPS-activated RAW264.7 macrophages with IC50 values of 16.13 ± 1.61 and 11.74 ± 0.26 μ M, respectively, making them more potent than the positive control (L-NMMA, IC50 = 42.24 ± 0.68 μ M). Biosynthetically, a plausible cyclization mechanism to yield the scaffold of133135 via a series of W-M rearrangement and alkyl shift has been proposed (Fig. 16).[134]
Fig. 16. Proposed biosynthetic pathways for129130 and 133137 .
Niduterpenoids A (136 ) and B (137 ), isolated fromAspergillus nidulans , represent the first examples of sesterterpenoids with a highly congested hexacyclic 5/5/5/5/3/5 carbon skeleton. Their structures have been determined via a combination of spectroscopic data and single-crystal X-ray diffraction analyses.[135] Compounds 136 and137 are estrogen receptorα inhibitors, and 136 abolished 17-estradiol induced human breast tumor cell proliferation in a dose-dependent manner (IC50 = 11.42 ± 0.85 μ M). Furthermore, a plausible biosynthetic pathway for 136 and 137 has been proposed and involved in a series of cyclization and W−M hydride and alkyl shift reactions (Fig. 16).[135]
5. Triterpenoids
Triterpenes are a class of terpenoids with 30 carbons in the basic parent nucleus. They exist in plants in free form or as glycosides, and have various biochemical activities. Among them, three systematic reviews have covered the published data on triterpenoids isolated from all organisms from 2013 to 2015.[136-138] In recent years, many triterpenoids have been reported with unusual tetracyclic,[139-144]pentacyclic,[140, 145-149] and a few tricyclic ring systems.[150-153] Among them, a series of dimers bearing different scaffold have been designed and synthesized, and their anti-HCV entry activities have also been evaluated.[154]
Belamchinenin A (138 ), an unprecedented 6/5/6 fused tricyclic triterpenoid with a novel carbon skeleton, has been isolated from the rhizomes of Belamcanda chinensis .[151] The absolute configuration of tricyclic nucleus system has been unequivocally assigned by ECD calculation. In addition, 138exhibits cytotoxicity against NCI-H1650, HepG2, BGC 823, HCT-116, and MCF-7 cells with IC50 values of 2.48, 2.55, 4.47, 2.29, and 2.85 μ M, respectively.[151]Nototronesides A−C (139141 ), three triterpenoid saponins with a 6/6/9 fused tricyclic tetranordammarane carbon skeleton, have been isolated from the leaves of Panax notoginseng .[152]Moreover, 140 showed a moderate neuroprotective effect on serum deficiency-induced cellular damage.[152]
Fig. 17. Proposed biosynthetic pathway for 142 .
Ganolearic acid A (142 ), a hexanorlanostane triterpenoid with a 3/5/6/5 fused tetracyclic skeleton from Ganoderma cochlear , has been found using a LC-UV/MS screening approach.[155] The stereochemical structure has been established by spectroscopic data, 13C NMR and ECD calculations, and then a plausible biosynthetic pathway for142 has been given (Fig. 17).[155]Alismanin A (143 ), a novel protostane-type triterpenoid with a C34 skeleton, has been isolated from the rhizomes ofAlisma orientale .[156] Its structure has been determined by a combination of HRESIMS, 2D NMR spectra, ECD calculation. 143 displayed significant agonistic effects on pregnane X receptor at a concentration of 10 nM.[156] Colqueleganoids A (144 ) and B (145 ), with the first methyl-30 incorporated 6/6/6/6 tetracyclic carbon skeleton, have been isolated from the root of Colquhounia elegans .[157]Interestingly, 144 and 145 showed significant immunostimulatory effects and enhanced the production of cytokines TNF-α and IL-6 in the RAW 264.7 cells stimulated with LPS.[157]
Applanoids A−E (146150 ) represent the first example ofGanoderma triterpenoids with 6/6/5/6/5 pentacyclic system and the formation of the ether ring between C-15 and C-20 involves Michael addition reaction.[158] Among of them,146 , 147 , and 148 could significantly activate human pregnane X receptor (hPXR), and molecular docking revealed that they were docked well into the ligand binding domain by the establishment of hydrogen bonds and van der Waals effects.[158] Irpexolidal (151 ), a triterpenoid with an unprecedented 6/5/6/5/6/5 fused polycyclic skeletal system carbon skeleton, has been isolated from the fruiting bodies of the medicinal fungus Irpex lacteus .[159] The structure of 151 has been established by ECD calculation, and DP4+probability based on GIAO NMR chemical shift calculations.[159]
Belamchinanes A−D (152155 ), four triterpenoids with an unprecedented 4/6/6/6/5 pentacyclic system, have been isolated from the seeds of Belamcanda chinensis .[160] Biological studies reveal that they have dose-dependently protect age-related renal fibrosis invitro . In addition, a key step of plausible biosynthetic pathway would involve in Michael addition reaction of the 3,4-secofernane (Fig. 18).[160] Alstoscholarinoids A (156 ) and B (157 ), representing new subtypes of pentacyclic triterpenoids, with unique 6/6/6/7/5 and 6/6/5/6/6/6 ring systems have been isolated from Alstonia scholaris .[161] Their absolute structures have been established by single-crystal X-ray diffraction, and ECD calculations. Surprisingly, both compounds exhibited potent antihyperuricemic bioactivity in vitro and invivo .[161]
Fig. 18. Proposed biosynthetic pathway for152155
Schincalactones A (158 ) and B (159 ), featuring a unique 5/5/6/11/3 fused schinortriterpenoids with a 13-membered carbon ring system, have been obtained from Schisandra incarnata .[162] The absolute configuration of158 has been confirmed by single-crystal X-ray diffraction, and then a plausible biosynthetic pathway for 158 and 159via 8,9-oxidative cleavage has been given (Fig. 19). Moreover, schilancidilactone C (160 ), representing the first 3-norlancischiartane with unusual configurational inversions occurring at C-1 and C-10 compared to the reported schindilactones A−C, has been isolated from Schisandra lancifolia .[163, 164]
Dichagelinoids A−E (161165 ) have been isolated and characterized by solid data from Dichapetalum gelonioides .[165] Particularly,161163 showed significant cytotoxic activities against A549 and HL-60 cells with IC50 values ranging from 1.00 to 1.35 μ M and 0.38 to 4.23μ M, respectively.[165]
Phainanolide A (166 ), a highly modified triterpenoid incorporating an unprecedented 6/9/6 heterotricyclic system in the down-left and a highly oxygenated 5,5-spirocyclic ketal lactone motif in the up-right, has been isolated from Phyllanthus hainanensis .[166] Particularly, 166exhibited potent activity against HL-60 cell lines with IC50 values of 0.079 ± 0.037 μ M, compared to that of the positive control (Adriamycin, IC50 = 0.073 ± 0.015 μ M).[166]
Fig. 19. Proposed biosynthetic pathway for 158 and