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P035. New compounds against ulcerative colitis through molecular topology

M. Galvez-Llompart1, M. Recio2, R. Garcia-Domenech1

1University of Valencia, Department of Physical Chemistry, Burjassot (Valencia), Spain; 2University of Valencia, Department of Pharmacology, Burjassot (Valencia), Spain

Background: The QSAR based upon molecular topology, is a formalism built on describing the molecules by means of topological descriptors. This formalism has been used here to the search of active compounds against ulcerative colitis (UC). IL‑6 plays a key role in the uncontrolled intestinal inflammatory process [1].

Methods: Four compounds with potential activity versus UC were selected by our topological model [2]. They were tested in vitro (Caco‑2 and RAW 264.7 cells) and in vivo (acute UC model induced by 5% dextran sulphate sodium (DSS)). Control group received no treatment. Products were orally administered (50 mg/kg) at days 0, 2, 4 and 7.

Table 1. Scoring system to calculate the Disease Activity Index (DAI)
ScoreWeight lossStool consistencyVisible blood in feces
26–10LooseSlight bleeding
4>20DiarrheaGross bleeding

Results: See Figures 1 and 2 and Table 2.

Figure 1. IL‑6 secretion by proliferating Caco‑2 cells were stimulated for 24 h with inflammatory stimuli.

Figure 2. IL‑6 secretion by RAW 264.7 cells were stimulated for 24 h with LPS.

DAI, Disease Activity Index.
*5/6, **4/6 and ***2/6 animals die during the UC's protocol at day 8.
Table 2
GroupWeight lossStool consistencyVisible blood in fecesTotal DAI score
AMA3  3
Calcein**42 6
DLT***3  3
RO 41–09604 26

Conclusions: According to the results, 3 out of 4 compounds were able active in vitro, and 2 of them (Ro 41–0960 and DLT) had also been revealed as a preventive compounds in vivo.

1. Atreya, R.; Neurath, M. F. (2005), Involvement of IL‑6 in the pathogenesis of inflammatory bowel disease and colon cancer, Clin Rev Allerg Immu

2. Gálvez-Llompart, M.; Recio, M. C.; García-Domenech, R. (2011), Topological virtual screening: a way to find new compounds active in ulcerative colitis by inhibiting NF-kappaB., Mol. Divers

3. Recio, M. C.; Gálvez-Llompart, M.; Zanni, R; García-Domenech, R. (2011), New Inhibitors of Il‑6 Production In Caco‑2 Cells Through Molecular Topology Methodology, XXXIII Congreso de la Sociedad Española de Farmacología, Málaga (Spain).