Synthesis And Activity Of Erythromycin Derivatives

Erythromycin has been widely used in the clinic for more than 50 years. Besides anti-microbial effects, erythromycin and its derivatives had been reported to have some other activities, such as prokinetic activity, anti-inflammatory activity, luteinizing hormone-releasing hormone antagonistic activity and phosphodiesterase-3 inhibitory activity. Recently, they had been discovered helpful effects on the treatment of tumor.Dimmer of erythromycin. a novel class of erythromycin derivative, was discovered in our forepart study. Further investigation proved that this compound had moderate antitumor activity in vitro. Therefore we picked it as the lead compound and through structural modification at the C-3, C-5, C-6 and C-9 positions, 17 novel compounds were designed and synthesized.Following the reported methodologies, 12 important intermediates including the N-monodemethyled erythromycin derivatives, 9（E）-oxime erythromycin derivatives, and 3-OH erythromycin derivatives, were prepared and purified. The synthesis of TL-001 to TL-003 was accomplished through 3’-N-alkylation by treatment of the N-monodemethyled derivatives with 1 -bromo-2-chloroethane. Compounds TL-004 to TL-005 and their simplified analogues TL-007 to TL-010 were prepared by utilizing chloracetyl chloride as acylation agent or/and alkylation agent.In addition to N-N linked erythromycin derivative dimmers, two other series of compounds including TL-006 and its simplified analogues TL-011 to TL-017 which were linked at C-9, had been prepared through the alkylation at the C-9 of erythromycin 9（E）-oxime or clarthromycin 9（E）-oxime by 1,4-dibromo-2-butene.All of 17 compounds’ chemical structures were characterized by the applications of ¹H NMR, ¹³C NMR and MS. The data of ¹³C NMR spectra were discussed briefly.9 of the target products were evaluated for their in vitro antitumor activities against human SGC-7901 and human HT-1080 cell lines by MTT assay. The results obtained in test demonstrated that most of the compounds were active in this assay.