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Antimicrobial and Lytic Activity of Squalamine Aminosterols and Efforts to Synthesize Analogs

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Description: The antimicrobial activity of squalamine and three analogs, squalamine; 7β-squalamine MSI-1436; 7β-MSI-1436 has been analyzed using two main assays. These aminosterols vary in stereochemistry at C7 with squalamine and MSI-1436 possessing an axial -OH group while 7β-squalamine and 7β-MSI-1436 have an equatorial -OH group at C7. Also the polyamine chain at C3 varies with squalamine and 7β-squalamine possessing the shorter spermidine group while MSI-1436 and 7β-MSI-1436 have the longer and more cationic spemine group. Membrane lytic activity was assayed using LUVs made from the anionic dioleoylphosphatidylglycerol (DOPG) and the zwitterionic dioleoylphosphatidylcholine (DOPC) phospholipids. The minimum inhibitory concentration of the analogs was assessed against E. coli, E. faecalis, P. aeruginosa, and S. aureus using a redox resazurin assay. In general, both vesicle lysis and antimicrobial activity of the aminosterols are shown to improve with a longer polyamine chain at C-3. Analogs with a 7α-OH substitutent demonstrate greater antimicrobial activity than similar analogs with a 7β-OH substituent. The results suggest that the stereochemistry of the C7-OH group is important in aminosterol activation at the membrane surface. The synthesis squalamine analogs with varying stereochemistry at the C3 and C7 substitutents, and also in the length and composition of the polyamine at C3 was also attempted with the goal of further illustrating these differences would have on the antimicrobial activity of the analogs using the two above-mentioned assays. The synthetic goal was to duplicate a previously reported highly stereoselective and relatively short scheme of 9 steps using chenodeoxycholic and ursodeaxycholic bile acids as starting material.
Language: English
Format: Degree Work