3.2. Ent-kaurane
The simplest ent -kaurane diterpenoid,ent -kaurane
(63 ),[87] was identified from the genusAgathis in 1961. The plant is locally called kauri pine ,
therefore the diterpenoid with negative optical rotation was calledent -kaurane. Up to now, more than 1000 ent -kaurane
diterpenoids have been isolated,[88] and most of
them are derived from the genus Isodon .[89]
Maoeriocalysin A (64 ),[90] a novel
rearranged ent -kaurane diterpenoid with an unprecedented
4,5-seco -3,5-cyclo-7,20-epoxy-ent -kaurane skeleton, have
been isolated from Isodon eriocalyx . Another highly rearranged
and dual-bridged spiro ent -kaurane diterpenoid crokonoid A
(65 ) has been isolated from Croton
kongensis .[91] 65 has displayed strong
cytotoxicity against HL-60 and A-549 cell lines. Pierisketolide A
(66 ) and pierisketones B and C (67 and 68 ),
three diterpenoids with an unusual
A-homo -B-nor -ent -kaurane carbon skeleton, have been
obtained from the roots of Pieris
formosa .[92] 66 exhibited an analgesic
effect with a 45% writhe inhibition rate at a dose of 10.0 mg/kg.
Grayannotoxane diterpenoids with a 5/7/6/5 ring system are derived from
the ent -kaurane, and their tetracyclic skeleton is formed by the
rearrangement of the kaurane A/B ring system to a 5,7-ring
system.[93, 94]
In recent years, Yao’s group has reported a serious of
grayanane diterpenoids from the
traditional Chinese medicineRhododendron mole .
Rhodomollacetals A−C
(69 −71 ),[95] three novel
diterpenoids with an unprecedented 2,3:5,6-di-seco -grayanane
carbon skeleton, have been isolated in 2017. The absolute configurations
of 69 and 70 have been assigned by single-crystal
X-ray crystallography, and 69 −71 show moderate PTP1B
inhibitory activities. Rhodomollanol A (72 ) also has been
reported in 2017,[96] which possesses a unique
3/5/7/5/5/5 hexacyclic ring system featuring a rare
7-oxabicyclo[4.2.1]nonane core decorated with three cyclopentane
units, and 72 exhibited moderate PTP1B inhibitory activity.
Furthermore, two highly modified grayanane diterpenoids,
mollebenzylanols A (73 ) and B
(74 ),[97] have been identified, and the
key steps of plausible biosynthetic pathway would involve in an
enzymatic W−M rearrangement and two retro-aldol reactions as shown in
Fig. 13. Three highly functionalized 5,6-seco -grayanane
diterpenoids mollactones A–C (75 –77 ) have been
reported in 2020,[98] and these compounds
exhibited significant PTP1B inhibitory activity. In 2021,
epoxymicranthol G (78 )[99] has been
obtained from Rhododendron micranthum , which is a
5,9‐epoxygrayanane diterpenoid expressed potent analgesic activity. The
structure‐activity relationship for the analgesic effects of
5,9‐epoxygrayanane diterpenoids has been discussed, and the
3β ‐OH, 10α ‐OH, 14α ‐OH, and 16α ‐OH may be the
activating groups to the analgesic activity of 5,9‐epoxygrayanane
diterpenoids. Bismollether A (79 ), a dimeric grayanane
diterpenoid with a caged structrue has been isolated in
2022,[100] and it exhibits significant analgesic
activities. An unprecedented 5/6/6/5 tetracyclic grayanane-derived
diterpenoid rhomollone A (80 ) has been obtained from flowers ofRhododendron molle. [101]
Fig. 13. Proposed biosynthetic pathway for73 −74 .
3.3.
Cembrane
Cembranolides, with a 14-membered
macrocyclic skeleton, are the precursors of casbane, tigliane, and
related diterpenoids.[102] (±)-Mangelonoids A and
B (81 –84 ),[103] two pairs of
enantiomers featuring an unprecedented bicyclo[9.3.1]pentadecane
core and a bridgehead double bond, have been isolated from Croton
mangelong . 81 exhibited NF-κ B inhibition with an
IC50 value of 7.27 ± 1.30 μ M. A novel cembranoid,
sarcomililate A (85 ),[104] possessing a
previously undescribed
tricyclo[11.3.0.02,16]hexadecane scaffold, has
been isolated from Sarcophyton mililatensis . Populusene A
(86 ) is a cembrane-type diterpenoid possessing an unprecedented
carbon skeleton,[105]western blotting analysis has
confirmed that 86 significantly inhibits LPS-induced activation
of NF-κB in RAW264.7 cells. Sinudenoid A
(87 ),[106] a new furanobutenolide-derived
C19-norcembranoid diterpene, has been isolated from the
soft coral Sinularia densa . Recently, several casbane-type
diterpenoids have been reported,[107-112] and
sinunanolobatone A (88 ) from Sinularia
nanolobata ,[107] featuring an unprecedented
casbane related carbon framework, showed significant inhibitory activity
against lipopolysaccharide (LPS) induced inflammation.