title: Generation of anti-trypanosomal agents through concise synthesis and structural diversification of sesquiterpene analogues.
abstract: To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp(3) ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine.
authors.affiliation: Division of Chemistry, Graduate School of Science, Creative Research Institution, Hokkaido University, North 21, West 10, Sapporo 001-0021, Japan. oguri@sci.hokudai.ac.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oguri
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hiruma
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oikawa
authors.forename: Aki
authors.initials: A
authors.lastname: Ishiyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Otoguro
authors.forename: Haruki
authors.initials: H
authors.lastname: Yamada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
mesh_terms: D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D037621:Artemisinins; D012717:Sesquiterpenes; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents