16-Membered Macrolide Lactone Derivatives Bearing a Triazole-Functionalized Arm at the Aglycone C13 Position as Antibacterial and Anticancer Agents

• Published in: ChemMedChem 2016-09, Vol.11 (17), p.1886-1891
• Main Authors: Domagalska, Joanna, Janas, Anna, Pyta, Krystian, Pecyna, Paulina, Ruszkowski, Piotr, Celewicz, Lech, Gajecka, Marzena, Bartl, Franz, Przybylski, Piotr
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotics; anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bacteria - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; drug-ribosome models; Humans; lactone macrolides; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; leucomycins; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600250

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. Ribosomal roadblock: Results of molecular docking studies with a ribosome structure from halophilic bacteria species, in combination with experimentally determined lipophilicity and aqueous solubility values along with antibacterial assays have demonstrated the importance of the nature of groups appended to the C13 arm of the macrolide lactone aglycone shown. This information will aid the future design of drug candidates among 16‐membered macrolides.