Squalamine (3�-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane}-7a,24R-dihydroxy-5a-cholestane-24-sulfate), an aminosterol from the dogfish shark Squalus acanthias, is a potent antimicrobial compound believed to act through plasma membrane lysis. In this report, the synthesis of a series of squalamine analogs is described, and their antimicrobial activity characterized using two different assays. The synthesized analogs vary in the stereochemistry at the 3- and 7- substitutents, and also in the length and composition of the polyamine added at C-3. The antimicrobial activity of the analogs was assessed against four bacterial strains. Membrane lytic activity was assayed using large unilamellar vesicles encapsulating a fluorescent calcein dye. Both vesicle lysis and antimicrobial activity of the aminosterols are shown to improve with a longer polyamine chain at C-3. Also, analogs with a 7a-OH substitutent are more potent than their 7�-OH analogs. The results suggest that the stereochemistry of the C7-OH group is important in aminosterol activation at the membrane surface.

Antimicrobial and lytic activities of squalamine analogs: Effect of stereochemistry at C3 and C7

244th National Meeting (2012)

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