Synthesis and biological activity of aminoacyl analogs of ascamycin.

Abstract

L-Prolyl and other aminoacyl derivatives of ascamycin (1) were synthesized by a condensation reaction of N6-t-butyloxycarbonyl-2-chloro-9-(2', 3'-O-isopropylidene-5'-O-sulfamoyl-β-D-ribofuranosyl)adenine (9) with the corresponding t-butyloxycarbonylaminoacylimidazole in the presence of Cs2CO3 in DMF as the key step. The L-prolyl derivative (2) and L-phenylalanyl derivative (3) as well as 1 showed selective toxicity against Xanthomonas citri. The L-prolyl-L-prolyl derivative (5) as well as dealanylascamycin (6) showed broad toxicity against various Gram-negative and Gram-positive bacteria. The D-alanyl derivative (4) lost its antibacterial activity. 2 was the best substrate (15.3M/min per mg of protein) for an Xc-aminopeptidase (an ascamycin-dealanylating enzyme from X. citri cells) among these analogs. This enzyme scarcely hydrolyzed 4 (0.2 M/min per mg of protein). The substrate specificity of the enzyme accounts for antibacterial activity of the analogs. 2 showed greater selective toxicity against Kirsten sarcoma virus transformed Balb3T3 (KN-3T3) cells than against nontransformed cells (Balb 3T3).