title: Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.
abstract: Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired.
authors.affiliation: Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, 1024 Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Myint
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiological and Nanobiomedical Engineering, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Bucki
authors.affiliation: Institute for Medicine and Engineering, Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
authors.affiliation: Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, 1024 Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: sld@seas.upenn.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D005938:Glucocorticoids / Q000138:chemical synthesis / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D002412:Cations; D005938:Glucocorticoids; D008055:Lipids
keywords: Anti-inflammatory; Antimicrobial; Cationic lipids; Cystic fibrosis; Lipofection