Synthesis, Antibacterial, and Anticancer Evaluation of Novel Spiramycin-Like Conjugates Containing C(5) Triazole Arm

• Published in: Journal of medicinal chemistry 2016-09, Vol.59 (17), p.7963-7973
• Main Authors: Klich, Katarzyna, Pyta, Krystian, Kubicka, Marcelina M, Ruszkowski, Piotr, Celewicz, Lech, Gajecka, Marzena, Przybylski, Piotr
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cycloaddition Reaction; Drug Screening Assays, Antitumor; Gram-Positive Bacteria - drug effects; Humans; Microbial Sensitivity Tests; Models, Molecular; Solubility; Spiramycin - analogs & derivatives; Spiramycin - chemical synthesis; Spiramycin - chemistry; Spiramycin - pharmacology; Structure-Activity Relationship; Thermodynamics; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00764

Huisgen cycloaddition allowed obtaining of novel triazole-bridged antibiotics (6–16) with the reconstructed C(5) arm of spiramycin. 1H–1H NOESY couplings indicated the structure of novel derivatives in solution and demonstrated that the rebuilt C(5) arm is slightly differently oriented relative to the aglycone part if compared to that of spiramycin (1). Combined analysis of biological data together with experimentally determined lipophilicity (clogP) and solubility show the importance of the chemical nature of the newly introduced triazole C(5) arm in the presence of attractive antibacterial and anticancer potency. The most cytotoxic active triazole conjugates having a hydrophobic and bulky C(5) arm showed higher selectivity toward cancer cell lines (HeLa, KB, MCF-7, Hep-G2, and U87) relative to HDF normal cells than that of the parent spiramycin. Our studies have demonstrated that the aldehyde group is not crucial for the presence of interesting antibacterial [MIC(S. pneumoniae) ∼ 1.2 μM] and anticancer [IC50(HepG2) ∼ 6 μM] properties of 16-membered lactone macrolides based on spiramycin’s aglycone.