Synthesis And Bioactivity Of Erythromycin Derivatives

Erythromycin, a 14-membered macrolide antibiotic, had been extensively used in the clinic for more than 50 years. In addition to the anti-microbial effects, erythromycin and its derivatives showed some other activities, such as prokinetic activity, anti-inflammatory activity, luteinizing hormone-releasing hormone antagonistic activity and phosphodiesterase-3 inhibitory activity. Moreover, they had been discovered to have some beneficial effects on the treatment of tumor.In our previous work, dimmers of erythromycin and their simplified analogues were discovered, which were found to have antitumor activity in vitro. Herein, two simplified analogues of dimmers of erythromycin (2-3 and 2-4) were selected as the lead compounds, and fourteen target compounds (TM-1～TM-14) were designed to investigate the structure-activity relationships for antitumor activity of erythromycin derivatives.Following the reported methodologies, fourteen synthetic intermediates (2-5-2-18) were prepared using erythromycin (1-1), roxithromycin (1-2), clarithromycin (1-3) or azithromycin (1-4) as starting materials by oximation, N-demethylation, hydrolyzation, N-alkylation or N-acylation. Target compounds (TM-1～TM-14) were synthesized via N-alkylation, O-alkylation or N-acylation of the intermediates, and characterized by the applications of MS,1H-NMR or 13C-NMR.All the target compounds were evaluated for their antitumor activities in vitro against human SGC-7901, KB and HT-1080 cell lines by MTT assay. Two target compounds (TM-5 and TM-9) showed significant antitumor activity with an IC50 of 1.0-10.0μM.In addition, a straightforward, microwave-assisted synthesis of erythromycin 11,12-cyclic carbonate, a useful 14-membered macrolide with antimicrobial activity, from erythromycin A in dioxane was accomplished in the absence of phase transfer catalyst (PTC) and its structure was characterized by MS and 1H-NMR. The present method was proved to be more convenient and effective to obtain erythromycin 11,12-cyclic carbonate compared with the conventional methods.