title: Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation.
abstract: β-Sitosterol and betulinic acid were used in designing their conjugates with selected polyamines bearing either an amide bond, or an ester and an amide bond simultaneously in the target molecule. The synthesized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is described separately for each of the three series of the target amides, because each series of compounds required a different synthetic approach. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with the tests on normal human fibroblasts. Most of the target compounds (5a-5c, 11a-11c and 16a-16c) showed medium to high cytotoxicity (0.7-7.8 μM), however, in some cases the compounds showed high cytotoxicity even toward normal human fibroblasts (11a-11c). Two compounds of this series (11c and 16c) also displayed antimicrobial activity with high and selective microbe specificity. The compound 11c was potent against Escherichia coli (minimal inhibition concentration (MIC) 6.25 μg mL(-1), i.e. 9.75 nM mL(-1)) and Staphylococcus aureus (MIC 12.5 μg mL(-1), i.e. 19.5 nM mL(-1)), and showed medium activity against Pseudomonas aeruginosa. The compound 16c was highly active against Enterococcus faecalis and S. aureus (both, MIC 3.125 μg mL(-1), i.e. 4.22 nM mL(-1)), both Gram-positive bacteria, however showed only weak activity against E. coli and no activity against P. aeruginosa, both Gram-negative bacteria, which indicates possible microbe specificity of 16c. Comparing β-sitosterol-based series (5a-5c) and betulinic acid series (11a-11c and 16a-16c) of the target compounds, the latter one gave more promising structures. The compounds 11c and 16c showed effects which may be described as multifarious activity (pleiotropic effects).
authors.affiliation: Institute of Experimental Botany AS CR, v.v.i., Isotope Laboratory, Vídeňská 1083, 14220 Prague 4, Czech Republic; Institute of Chemical Technology, Faculty of Food and Biochemical Technology, Department of Chemistry of Natural Compounds, Technická 5, 16628 Prague 6, Czech Republic.
authors.forename: Uladzimir
authors.initials: U
authors.lastname: Bildziukevich
authors.affiliation: Institute of Chemical Technology, Faculty of Food and Biochemical Technology, Department of Chemistry of Natural Compounds, Technická 5, 16628 Prague 6, Czech Republic.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vida
authors.affiliation: Institute of Experimental Botany AS CR, v.v.i., Isotope Laboratory, Vídeňská 1083, 14220 Prague 4, Czech Republic; Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 11, 78371 Olomouc, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Rárová
authors.affiliation: Department of Microbiology, Faculty of Medicine and Dentistry, Palacký University, Hněvotinská 3, 77515 Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Kolář
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nám. 2, 16610 Prague 6, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Šaman
authors.affiliation: Institute of Experimental Botany AS CR, v.v.i., Isotope Laboratory, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Havlíček
authors.affiliation: Institute of Chemical Technology, Faculty of Food and Biochemical Technology, Department of Chemistry of Natural Compounds, Technická 5, 16628 Prague 6, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Drašar
authors.affiliation: Institute of Experimental Botany AS CR, v.v.i., Isotope Laboratory, Vídeňská 1083, 14220 Prague 4, Czech Republic; Institute of Chemical Technology, Faculty of Food and Biochemical Technology, Department of Chemistry of Natural Compounds, Technická 5, 16628 Prague 6, Czech Republic. Electronic address: wimmer@biomed.cas.cz.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Wimmer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008826:Microbial Sensitivity Tests; D053978:Pentacyclic Triterpenes; D011073:Polyamines / Q000737:chemistry* / Q000633:toxicity; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012855:Sitosterols / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D000900:Anti-Bacterial Agents; D053978:Pentacyclic Triterpenes; D011073:Polyamines; D012855:Sitosterols; D014315:Triterpenes; C025473:gamma-sitosterol; D000094062:Betulinic Acid
keywords: Amide; Antimicrobial activity; Betulinic acid; Cytotoxicity; Polyamine; β-Sitosterol