title: Design, synthesis, and antibacterial activities of conformationally constrained kanamycin A derivatives.
abstract: A series of conformationally constrained kanamycin A derivatives with a 2'-hydroxyl group in ring I and a 5-hydroxyl group in ring II tethered by carbon chains were designed and synthesized. Pivotal 5,2'-hydroxyl groups were exposed, and the kanamycin A intermediate was synthesized from 5, 2', 4″, 6″-di-O-benzylidene-protected tetraazidokanamycin A. Cyclic kanamycin A derivatives with intramolecular 8-, 9-, 10-, and 11-membered ethers were then prepared by cesium carbonate mediated Williamson ether synthesis or a ring-closing metathesis reaction. The kanamycin A derivatives were assayed against both susceptible and resistant bacterial strains. Although no derivative showed better antibacterial activities than kanamycin A, the antibacterial activities of these cyclic kanamycin A derivatives indeed varied with the length of the bridge. Moreover, different variations of activities were observed between the susceptible and resistant bacterial strains. More tightly constrained derivative 2 with a one-carbon bridge showed better activity than the others against susceptible strains, but it was much less effective for resistant bacterial strains than derivative 3 with a two-carbon bridge and derivative 6 with an unsaturated four-carbon bridge.
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Qingzhao
authors.initials: Q
authors.lastname: Liang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Jin
authors.forename: Liangren
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiangbao
authors.initials: X
authors.lastname: Meng
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D007612:Kanamycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001952:Bridged-Ring Compounds; D007612:Kanamycin