title: Development of Novel Erythromycin Derivatives with Inhibitory Activity against Proliferation of Tumor Cells.
abstract: In our continuing structure-activity relationship study of a new class of erythromycin A (EM-A) derivatives with antiproliferative activity, a new series of de(N-methyl) EM-A dimers jointed by a four-atom linker, -CH2CH = CHCH2-, were prepared and their antiproliferative activity against three human tumor cell lines was evaluated by MTT assay. The most active EM-A dimer, compound 1b, that carrying C6 methoxyl groups was further investigated and showed potent antiproliferative activity in six other human tumor cell lines. Flow cytometry analysis of 1b treated HeLa and MCF-7 cells indicated that the four-atom EM-A dimers induced the SubG1 phase cell cycle arrest and cell apoptosis, in time- and dose-dependent manners. Further experiments including morphologic observation, DNA agarose gel electrophoresis, mitochondrial potential alternation and western blot analysis revealed that the antiproliferative mechanism may involve the induction of apoptosis in activating the mitochondrial pathway, and regulation of apoptotic proteins.
authors.affiliation: Department of Geratology, The First Affiliated Hospital of Chinese Medical University, Shenyang, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Bao
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Defa
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Geratology, The First Affiliated Hospital of Chinese Medical University, Shenyang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Weiyun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Weige
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Bin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D055808:Drug Discovery; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D004917:Erythromycin