Glycoglycerolipid analogues active in cancer chemoprevention: the role of the ester function on the inhibition of Epstein-Barr virus early antigen activation

F Ronchetti a, D Colombo Dr,a F Compostella Dr,a A Scala Prof,a Harukuni Tokuda Dr,b Hoyoku Nishino Drb

a Department of Chemistry and Medical Biochemistry, University of Milan, Via Saldini 50, 20133 Milan Italy; b Department of Biochemistry, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-0841, Japan.

AIM: Investigation of the structural features responsible for the anti-tumor-promoting effects of glycoglycerolipids, focusing in particular on the role that the acyl residue plays on their activity. Preparation of analogues structurally related to three acylglycosylglycerols characterized by a C6 fatty acid chain linked to the glycosylglycerol skeleton; these reference compounds, showing a remarkable inhibitory effect on tumor promotion induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) both in vitro and in vivo, are the most active chemopreventing glycoglycerolipids analogues so far known (Colombo et al., Cancer Letters 1999, 143, 1-4 and Cancer Letters 2000, 161, 201-205). METHODS: Nine new synthetic compounds, in which the ester moiety is replaced by a metabolically more stable ether, alkyl or keto chain, were tested for their anti-tumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus early antigen (EBV-EA) activation, and their potency compared with that of the corresponding esters. RESULTS: All the tested samples resulted significantly active in inhibiting the EBV-EA activation promoted by the tumor promoter TPA, their activity being strictly equivalent to that of the reference esters. CONCLUSIONS: The results indicate that the inhibitory effect is not influenced by the ester function, but, essential for the activity, is the presence of a lipophylic chain and not the way in which this chain is linked to the glycosylglycerol skeleton. These glycoglycerolipid analogues, which are more stable to digestive hydrolytic processes and non-cytotoxic, seem very attractive because of their potential therapeutic use as chemopreventing agents by oral administration.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.