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 (110 −112 ), 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 (133 −135 ), 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 of133 −135 via a series of W-M rearrangement and alkyl
shift has been proposed (Fig. 16).[134]
Fig. 16. Proposed biosynthetic pathways for129 −130 and 133 −137 .
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
(139 −141 ), 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 (146 −150 )
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
(152 −155 ), 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 for152 −155
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 (161 −165 ) have been isolated and
characterized by solid data from Dichapetalum
gelonioides .[165] Particularly,161 −163 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