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

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.