Discovery and development of natural product oridonin-inspired anticancer agents

Abstract

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Keywords: Anticancer agents; Chemical biology; Diterpenoids; Drug discovery; Natural product; Oridonin.

Fig. 1

A) Of the 112 FDA-approved first-in-class drugs from 1999 to 2013, 31 drugs (28%) originated from natural products and substances versus 47 drugs (42%) which are synthetic small molecules, and 34 drugs which are biological agents. B) The structure of the natural diterpenoid oridonin. C) Number of papers published between 2004 and 2014 containing the keyword “oridonin” according to the Web of Science search. D) Citations between 2004 and 2014 according to the Web of Science search using the keyword “oridonin”.

Fig. 2

Major milestones achieved in oridonin-inspired drug discovery and development.

Fig. 3

Oridonin regulates multi-signaling pathways to display corresponding multifunctional effects. A) and B). At low concentrations, oridonin regulates Keap1-Nrf2-ARE and NF-κB pathways to exert cytoprotective and anti-inflammatory effects. C). Elevated concentrations of oridonin inhibit proliferation and induce apoptosis by regulating ROS-mediated and other signaling pathways. These paradoxical activities may be correlated with partial signaling pathway modulation in different cell conditions and depend upon the dosage of treatment.

Fig. 4

The structures of C-1 and/or C-14 position modified oridonin derivatives.

Fig. 5

Diversified modifications on A-ring of oridonin template.

Fig. 6

Modifications on D-ring of oridonin.

Fig. 7

Biosynthetic pathway of oridonin secondary metabolites.

Fig. 8

Spirolactone-type diterpenoid derivatives generated from oridonin template.

Fig. 9

Enmein-type diterpenoid derivatives generated from oridonin.

Fig. 10

Synthesis of the kaurane-type diterpenoid rubescensin S starting from oridonin.

Fig. 11

Synthesis of kaurane-type pharmacophore in the structure of semiaquilegin A starting from oridonin.

Fig. 12

Graphical depiction of the general structure-anticancer activity relationship of oridonin derivatives based upon the available in vitro and in vivo biological results.