title: Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.
abstract: The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.
authors: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors: Shuangyi
authors: S
authors: Wan
authors: Fanghui
authors: F
authors: Wu
authors: Jason C
authors: JC
authors: Rech
authors: Michael E
authors: ME
authors: Green
authors: Raghavan
authors: R
authors: Balachandran
authors: W Seth
authors: WS
authors: Horne
authors: Billy W
authors: BW
authors: Day
authors: Paul E
authors: PE
authors: Floreancig
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D011714:Pyrans; D011753:Pyrones; C498383:psymberin; C100127:pederin