THE SYNTHESIS AND CHARACTERIZATION OF ANALOGS OF THE ANTIMICROBIAL COMPOUND SQUALAMINE - 6-BETA-HYDROXY-3-AMINOSTEROLS SYNTHESIZED FROM HYODEOXYCHOLIC ACID

Analogs of the aminosterol antimicrobial agent squalamine have been sy nthesized beginning from hyodeoxycholic acid. After carboxylic acid es terification and oxidation of both alcohol functions to ketones, the A /B ring junction was converted from cis to trans by acid-catalyzed iso merization. Different polyamines were added to the 3-keto group by red uctive amination, yielding both the 3 alpha and 3 beta addition produc ts. The synthetic products exhibited potent, broad-spectrum antimicrob ial activity similar to that of the parent compound. Changing the iden tity of the polyamine or the stereochemistry of addition has little ef fect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexp ensive starting materials and are promising alternatives to squalamine as potential antibiotics. (C) 1996 by Elsevier Science Inc.