| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Recent developments in the area of cell adhesion are playing important roles in the molecular elucidation of inflammation and metastasis. Compounds with inhibitory actions on cell adhesion have been used as candidates for new anti-inflammatory and anti-metastatic drugs. The fundamental concept of the present project involves the known but less understood varsatility of lipophilic sugar derivatives that could exist as any possible shape of molecules and be available nowadays via new synthetic ways and modification of naturally occuring sugars. The purpose of this project is therefore to search for novel lipophilic sugar derivatives inhibiting cell adhesion of leucocyte and cancer cells, to examine their mode of action, and to apply findings obtained to the development of newer and novel bioactive sugars. Methods of screening tests used included the inhibition by sugar derivatives of adhesion of neutrophils to KLH and HUVEC,of generation of active oxygen species, and of experssion of adh
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esion molecules such as ICAM-1 and ELAM-1. Some in vivo inflammation models were used to evaluate in vitro active compounds. Of more than 500 mono-, oligo, and polysaccharide derivatives, seven lipophilic compounds were found to exhibit the most active inhibitory actions against the above three tests and in vivo test of oxazolone-induced edema of mouse. Tri-O-benzoyl-D-ribose derivatives were chosen as the main target of the present project, named TK-50p, TK-50f, and TK-50m, respectively, and subjected to detailed studies. Modification of substituents, sugar skeleton and lipophilicity of TK-50 revealed that the benzyl groups are also very effective and that configuration change from ribo into xylo or arabino is effective, as well. These results suggest that some more active and stable derivatives may be prepared by modification of natural polysaccharides. TK-50 and other lead compounds exhibited inhibitory action against delayd hypersensitivity of mouse. This in vivo activity was interestingly different from that of tribenoside in that the latter activity was effective in arachidonic acid-or TPA-induced mouse car edema. The tribenzoyl riboses exhibited anti-invasive action towards fibroblastoma HT1080, but no cytotoxicity was observed at the concentration of 10^<-4>M,as determined by LDH assay on neutrophils. No concrete mechanism has been establishied for the antiadhesion activity of these ribose sugars. No inhibition was observed in the assays for protein kinases, metaroproteinases, and formation of tubuluin. In vivo antimetastasis experiments are in progress uing breast cancer cells. Less
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