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 (6971 ),[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 6971 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 (7577 ) 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 for7374 .
3.3. Cembrane
Cembranolides, with a 14-membered macrocyclic skeleton, are the precursors of casbane, tigliane, and related diterpenoids.[102] (±)-Mangelonoids A and B (8184 ),[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.