Synthesis, anticancer and antibacterial evaluation of novel spiramycin-acylated derivatives†

Abstract

Spiramycin and its derivatives are commonly used antimicrobials, and its derivative, carrimycin, has recently been found to have good anticancer potential. Here, we found that the 4′′-OH of spiramycin can be selectively acylated, resulting in a series of novel spiramycin derivatives with a structure similar to carrimycin. Anticancer studies showed that most of the derivatives exhibited moderate to good anti-proliferative activity against four cancer cell lines, including HGC-27, HT-29, HCT-116 and HeLa, especially compound 14, which has the strongest activity against HGC-27 cells with an IC₅₀ value of 0.19 ± 0.02 μM. Pharmacological studies on HGC-27 cells revealed that compound 14 could arrest the cell cycle in the S phase, raise ROS levels, and induce cell apoptosis via activation of Erk/p38 MAPK signaling pathways. In addition, antibacterial studies showed that most of the spiramycin I derivatives modified at the 4′′-OH group enhanced antibacterial activity on the four tested strains, including S. aureus, S. aureus MRSA, S. epidermidis, and B. subtilis. In particular, compound 16 was the most effective one and comparable to linezolid, a commonly used first-line antimicrobial. These results suggest that spiramycin I derivatives may provide an opportunity to design new anticancer or antibacterial agents, even dual-function agents.