title: Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?
abstract: It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
authors.affiliation: Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences Hokkaido University, Kita-12 Nishi-6 Kita-ku, Sapporo, 060-0812, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D016983:Enterococcus / Q000187:drug effects; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D007555:Isoxazoles; D009705:Nucleosides; D010080:Oxazoles; C064210:oxazolidine
keywords: antibiotics; function-oriented synthesis; natural products; nucleosides; synthesis design