NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

Abstract

A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a-i) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC 50 of 0.81 µM and could also release 33.7 µmol/L NO at the time point of 60 min. Compounds 10a-i also showed cytotoxic selectivity between tumor and normal liver cells with IC 50 ranging from 22.1 to 33.9 µM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations.

Enmein Decreases Synaptic Glutamate Release and Protects against Kainic Acid-Induced Brain Injury in Rats

“…Diterpenoids are important and widely distributed natural compounds with various biological effects, including antitumor, anti-inflammatory, and immune modulation effects [ 32 ]. Enmein is a diterpenoid extracted from Isodon japonicus Hara that exhibits antitumor, anti-inflammatory, and immune modulation effects [ 16 , 17 , 33 ]. The present study provides the first description of the role of enmein in the central glutamate system, including its ability to regulate glutamate release from rat cerebrocortical nerve terminals and exhibit neuroprotective effects in a rat model of KA-induced glutamate excitotoxicity.…”

“…Enmein is a diterpenoid derived from the plant Isodon japonicus Hara that is widely used in dietary supplements and folk medicine [ 14 ]. Enmein has antibacterial [ 15 ], anti-inflammatory [ 16 ], antitumor [ 17 ], and immunosuppressive effects [ 18 ]. There is currently no data to support the effects of enmein on the central glutamate system.…”

Daphnoretin induces reactive oxygen species‑mediated apoptosis in melanoma cells

“…Apoptosis is a complex process in which various protein signals are transmitted through several different pathways (25). Caspases, which are the convergence points of multiple apoptotic pathways, regulate the final execution of apoptosis (26,27). Thus, caspase activation is an essential link in apoptotic signal transduction (28).…”

Bioactive Natural Spirolactone-Type 6,7-seco-ent-Kaurane Diterpenoids and Synthetic Derivatives

“…Natural products have been used to treat various diseases in China for hundreds of years. Their novel molecular skeletons and promising cytotoxic activities are invaluable sources for drug discovery and development processes [ 1 , 2 , 3 , 4 ]. Natural products have played crucial roles in drug discovery.…”