Abstract
Several sesquiterpene lactones (STLs) have been tested as lead drugs in cancer clinical trials. Salograviolide-A (Sal-A) and salograviolide-B (Sal-B) are two STLs that have been isolated from Centaurea ainetensis, an indigenous medicinal plant of the Middle Eastern region. The parent compounds Sal-A and Sal-B were modified and successfully prepared into eight novel guaianolide-type STLs (compounds 1–8) bearing ester groups of different geometries. Sal-A, Sal-B, and compounds 1–8 were tested against a human colorectal cancer cell line model with differing p53 status; HCT116 with wild-type p53 and HCT116 p53−/− null for p53, and the normal-like human colon mucosa cells with wild-type p53, NCM460. IC50 values indicated that derivatization of Sal-A and Sal-B resulted in potentiation of HCT116 cell growth inhibition by 97% and 66%, respectively. The effects of the different molecules on cancer cell growth were independent of p53 status. Interestingly, the derivatization of Sal-A and Sal-B molecules enhanced their anti-growth properties versus 5-Fluorouracil (5-FU), which is the drug of choice in colorectal cancer. Structure-activity analysis revealed that the enhanced molecule potencies were mainly attributed to the position and number of the hydroxy groups, the lipophilicity, and the superiority of ester groups over hydroxy substituents in terms of their branching and chain lengths. The favorable cytotoxicity and selectivity of the potent molecules, to cancer cells versus their normal counterparts, pointed them out as promising leads for anti-cancer drug design.
Highlights
Terpenes have attracted considerable attention of medicinal chemists due to their numerous biological activities [1,2]
This is the first report of Sal-B purified from C. ainetensis, it has been found in other Asteraceae plants [31,32,34,35,36]
A series of eight new guaianolide-type sesquiterpene lactones (STLs) derivatives were synthesized with ester group(s) modification at either C8-OH, C9-OH, or both, positions
Summary
Terpenes have attracted considerable attention of medicinal chemists due to their numerous biological activities [1,2]. Sesquiterpene lactones (STLs) are a group of compounds commonly isolated from various genera of the Asteraceae family and are known to possess diverse biological activities [3]. The biological activity of these complex plant secondary metabolites appears to be associated with their ability to act as alkylating agents due to a Michael addition reaction by biological nucleophiles to the α-methylene part of the lactone moiety [5,6]. It was postulated that the reactions between α-methylene-γ-lactone and other conjugated systems with biologically crucial sulfhydryl groups may play a significant role in the mechanism by which these compounds exert their biological activities [7]. STLs may exert their biological effects by inhibiting cellular enzyme activity and not by alkylating or impairing DNA function [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
