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 synthesized beginning from hyodeoxycholic acid. After carboxylic acid esterification and oxidation of both alcohol functions to ketones, the A/B ring junction was converted from cis to trans by acid-catalyzed isomerization. Different polyamines were added to the 3-keto group by reductive amination, yielding both the 3 alpha and 3 beta addition products. The synthetic products exhibited potent, broad-spectrum antimicrobial activity similar to that of the parent compound. Changing the identity of the polyamine or the stereochemistry of addition has little effect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexpensive starting materials and are promising alternatives to squalamine as potential antibiotics.
Department of Chemistry, Villanova University, Pennsylvania 19085, USA.
S R
SR
Jones
W A
WA
Kinney
X
X
Zhang
L M
LM
Jones
B S
BS
Selinsky
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology; D002793:Cholic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000737:chemistry*; D003902:Detergents / Q000737:chemistry; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
C104304:6-hydroxy-3-(N(1)-sperminyl)-5alpha-cholan-24-oic acid; D000900:Anti-Bacterial Agents; D002777:Cholestanols; D002793:Cholic Acids; D003902:Detergents; D005029:Ethylenediamines; C104303:methyl 3-(aminoethylamino)-6-hydroxy-5alpha-cholan-24-oate; D003840:Deoxycholic Acid; D013096:Spermine; C010471:hyodeoxycholic acid; C079655:squalamine