title: 16-Membered Macrolide Lactone Derivatives Bearing a Triazole-Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents.
abstract: A series of new C13-triazole-bridged and C13-ether leucomycin analogues with a reduced aldehyde group were synthesized. Derivatives with the highest antibacterial [MIC values (S. epidermidis, S. pneumoniae): ∼2-4 μg mL(-1) ; 2.55-5.09 μm] and cytotoxic [IC50 values (HeLa, KB, MCF-7, A549, HepG2 cells): ∼1.35-3.70 μm] potencies were those with the best aqueous solubility and bearing a saccharide-triazole arm at the C13 position of the aglycone. These derivatives preferentially bind at the ribosomal tunnel and show the most attractive selectivity indexes [SI; calculated relative to the human dermal fibroblast (HDF) cell line], even higher than that of the reference compound cytarabine. Results of molecular docking studies of this type of macrolide antibiotics at the ribosomal tunnel, together with experimentally determined lipophilicity and aqueous solubility values, as well as biological assay data revealed the importance of the introduced functional group at the aglycone C13 arm to the future design of anticancer and antibacterial drug candidates. Our results clearly indicate that the high antibacterial and anticancer activities of these types of macrolides do not necessarily depend on the presence of the aldehyde group at the aglycone lactone ring.
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Domagalska
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janas
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznan, Poland.
authors.forename: Krystian
authors.initials: K
authors.lastname: Pyta
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4, 60-781, Poznan, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Pecyna
authors.affiliation: Department of Pharmacology, University of Medical Sciences, Rokietnicka 5a, 60-806, Poznan, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruszkowski
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznan, Poland.
authors.forename: Lech
authors.initials: L
authors.lastname: Celewicz
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4, 60-781, Poznan, Poland.|Institute of Human Genetics, Polish Academy of Science, Strzeszynska 32, 60-479, Poznan, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Gajecka
authors.affiliation: Institut für Medizinische Physik und Biophysik (CC2), Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.|Zentrum für Biophysik und Bioinformatik, Humboldt-Universität zu Berlin, Invalidenstrasse 42, 10115, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bartl
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614, Poznan, Poland. piotrp@amu.edu.pl.
authors.forename: Piotr
authors.identifier: 0000-0001-8072-5877
authors.initials: P
authors.lastname: Przybylski
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D007783:Lactones; D014230:Triazoles
keywords: antibiotics; anticancer agents; drug-ribosome models; lactone macrolides; leucomycins