Targeted modification of trilobolide and search for related sesquiterpenes with immunobiological properties

Trilobolide and its analogues belong to guaianolide type of sesquiterpene lactones, widely distributed within families Asteraceae and Apiaceae [1]. Trilobolide (1), structurally related to thapsigargin (4), is quite specific in its structure and biological activities [2]. Certain guaianolides evoked attention for their promising anti-inflammatory, anticancer, anti-infectious and SERCA inhibitory activities. However, due to their alkylation capabilities, they are generally toxic. Search for compounds with significant immunobiological properties, but with minor cytotoxicity is a challenge for immunopharmacological research also in our case [3].

(Fig.1)

We extended investigation of the immune interventions of trilobolide [2, 3] also on related guaianolides (2–7) isolated either from Laser trilobum (L.) Borkh., or from related Laserpitium siler (L.). For the structure-activity relationship study, we included also a series of structurally related exomethylene lactones (e.g. well recognised helenalin) [1]. For better relationship evaluations, additional series of transformed deacyl derivatives were prepared, either by alkaline hydrolysis or by hydrogenolysis of trilobolide. Implication of the specific vicinal diol (glycol), located on the lactone moiety, combined with the presence of various esters or other structure functionalities, is particularly assessed and evaluated.

Keywords: sesquiterpenes, guaianolides, trilobolide, structure-activity relationship, immunomodulation, Laser trilobum

Figure 1

Acknowledgement: Supported by GACR grant No 305/07/0061

References: 1. Holub M et al. (1986) Phytochemistry 25: 2015–2026.

2. Kmoníčková E et al. (2008) Eur J Pharm 588: 85–92.

3. Kmoníčková E et al. (2010) Fitoterapia 81: 1213–1219.