Covering: 1990 to 2015 The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented.

P-glycoprotein (P-gp) plays a significant role in multi-drug resistance (MDR) of cancer cells, resulting in the failure of cancer chemotherapy. Lathyrane diterpene was a class of promising MDR modulator. The phytochemical investigation on the seeds of Euphorbia lathyris L. aff ;orded four new lathyrol-type diterpenoids (1-4), together with seventeen known ones (5-23). The structures of these compounds were elucidated by using 1D and 2D NMR spectroscopy. All the compounds were evaluated reversing MDR activity in HepG2/ADR cells. Compounds 2-4, 7-9, 11, 13-14, 16, 18-19, and 2 1-2 3 at 20 μM was able to reverse MDR of HepG2/ADR cells to adriamycin (reversal fold: 10.05-448.39). In the investigation of reversing the MDR mechanism, the most potent compound 21 facilitated the accumulation of intracellular adriamycin in HepG2/ADR cells in the time-dependent model. Although 21 neither affected the P-gp distribution nor expression in HepG2/ADR cells, the amount of P-gp monomer was induced by 21 and verapamil. Compound 21 has also activated the P-gp coupled ATPase activity in a dose-dependent model. The molecular docking analysis implied that 21 had lower binding energy than verapamil and adriamycin. The present data demonstrated that lathyrane diterpenes may act as a class of high-affinity P-gp substrate and was effluxed by P-gp monomer to reverse the MDR.