Luca Stucchi

Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: a preclinical study.

New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27kip1, p53 and p21waf1) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer.

Synthesis of 6-deoxy-6-halolaminarans and conversion of 6-chloro-6-deoxylaminaran into the 6-amino-6-deoxy derivative

Abstract The reaction of laminaran, a linear polyglucan with β -(1 → 3)-linkages 1 , with trityl chloride followed by conventional acetylation gave a product that contained predominantly 6- O -trityl-2,4-di- O -acetate ( 3 ). Detritylation using hot aqueous acetic acid afforded a product containing 2,6-di- O -acetate ( 4 ), 2,4-di- O -acetate ( 5 ), and 2,4,6-tri- O -acetate ( 6 ) glucosyl residues. Similarly, the 2,4-di- O -benzoate ( 8 ) was prepared and then converted to the 6-bromo-6-deoxy derivative ( 9 ), using triphenylphosphine and carbon tetrabromide. The benzoyl groups in 9 could not be removed completely under conventional conditions. Direct halogenation of laminaran ( 1 ) with triphenylphosphine and carbon tetrabromide was unsuccessful. The replacement of the primary hydroxyl groups in 1 by halogens was achieved using methanesulfonyl halide-DMF complex. Syntheses of the 6-bromo-6-deoxy-2,4-di- O -formate ( 10 ) and the 6-chloro-6-deoxy-2,4-di- O -formate ( 12 ) were thus achieved. The formyl groups in 10 and 12 were removed under mild basic conditions to afford 11 and 13 . Treatment of the 6-chloro-6-deoxy-2,4-di- O -formate derivative 12 with sodium azide in DMF afforded the free 6-azido-6-deoxy compound 14 . However, when 6-chloro-6-deoxylaminaran ( 13 ) was treated with sodium azide it gave a compound which contained both the azide and chloro groups at C-6 positions in the polymeric chain. Catalytic hydrogenation of the water soluble 6-azido-6-deoxy-2,4-di- O -succinyl derivative 15 to give the desired 6-amino-6-deoxy compound 16 was unsuccessful. Chemical hydrogenation using triphenylphosphine in DMF gave the intermediate 6-triphenylphosphinimine 17 , which on subsequent treatment with aq 30% ammonia afforded a compound containing both the 6-phosphinimino and the 6-amino groups. The structures of all the compounds were confirmed by 13 C NMR and by FTIR spectroscopy.