1.
Felth, Jenny, et al.
(författare)
Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
2009
Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 72:11, s. 1969-1974
Tidskriftsartikel (refereegranskat) abstract
Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.
2.
Rosén, Josefin, 1978-, et al.
(författare)
ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action
2009
Ingår i: QSAR & combinatorial science (Print). - : Wiley. - 1611-020X .- 1611-0218. ; 28:4, s. 436-446
Tidskriftsartikel (refereegranskat) abstract
A combined graph describing the growth inhibition values from a number of human cancer cell lines represents an activity profile for a compound. The fact that compounds with similar activity profiles often show similar mode of action (MOA) has frequently been used in prediction of MOA. Obtaining the profiles is demanding with respect to both time and resources. Therefore, as a work and time efficient alternative, we explore the central premise of medicinal chemistry that structurally similar molecules often have similar biological activity. In this study we investigate correlations between chemical structure and MOA, and subsequently use this as a complementing basis for prediction. The correlations between MOA and activity profile on one hand and between MOA and chemical structure on the other were analyzed for anticancer agents, classified with regard to MOA, using principal component analysis (PCA), chemographic mapping with ChemGPS-NP, and orthogonal partial least squares discriminant analysis (OPLS-DA). The compounds clustered according to MOA both based on chemical structures and activity profiles. The subsequent validation with external test sets showed that initial PCA scores prediction or chemographic mapping followed by OPLS-DA could be used for prediction of MOA as well as identification of novel MOAs in a highly accurate way. An efficient and straight forward procedure for prediction of MOA of anticancer agents is suggested. With today’s resistance problems in cancer therapy, there is a need for new anticancer agents and mechanisms. We believe that the fast initial virtual guidance this procedure implies, especially the novel step using ChemGPS-NP, could be of general use in early stages of cancer research.
3.
Wang, Conan, et al.
(författare)
Combined X-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold
2009
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:16, s. 10672-10683
Tidskriftsartikel (refereegranskat) abstract
Cyclotides are a family of plant defense proteins that are highly resistant to adverse chemical, thermal, and enzymatic treatment. Here, we present the first crystal structure of a cyclotide, varv F, from the European field pansy, Viola arvensis, determined at a resolution of 1.8 angstrom. The solution state NMR structure was also determined and, combined with measurements of biophysical parameters for several cyclotides, provided an insight into the structural features that account for the remarkable stability of the cyclotide family. The x-ray data confirm the cystine knot topology and the circular backbone, and delineate a conserved network of hydrogen bonds that contribute to the stability of the cyclotide fold. The structural role of a highly conserved Glu residue that has been shown to regulate cyclotide function was also determined, verifying its involvement in a stabilizing hydrogen bond network. We also demonstrate that varv F binds to dodecylphosphocholine micelles, defining the binding orientation and showing that its structure remains unchanged upon binding, further demonstrating that the cyclotide fold is rigid. This study provides a biological insight into the mechanism by which cyclotides maintain their native activity in the unfavorable environment of predator insect guts. It also provides a structural basis for explaining how a cluster of residues important for bioactivity may be involved in self-association interactions in membranes. As well as being important for their bioactivity, the structural rigidity of cyclotides makes them very suitable as a stable template for peptide-based drug design.
