title: Chemical and biological studies of nakiterpiosin and nakiterpiosinone.
abstract: Nakiterpiosin and nakiterpiosinone are two related C-nor-D-homosteroids isolated from the sponge Terpios hoshinota that show promise as anticancer agents. We have previously described the asymmetric synthesis and revision of the relative configuration of nakiterpiosin. We now provide detailed information on the stereochemical analysis that supports our structure revision and the synthesis of the originally proposed and revised nakiterpiosin. In addition, we herein describe a refined approach for the synthesis of nakiterpiosin, the first synthesis of nakiterpiosinone, and preliminary mechanistic studies of nakiterpiosin's action in mammalian cells. Cells treated with nakiterpiosin exhibit compromised formation of the primary cilium, an organelle that functions as an assembly point for components of the Hedgehog signal transduction pathway. We provide evidence that the biological effects exhibited by nakiterpiosin are mechanistically distinct from those of well-established antimitotic agents such as taxol. Nakiterpiosin may be useful as an anticancer agent in those tumors resistant to existing antimitotic agents and those dependent on Hedgehog pathway responses for growth.
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA.
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Gao
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Wang
authors.forename: Lily Jun-Shen
authors.initials: LJ
authors.lastname: Huang
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006718:Homosteroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013237:Stereoisomerism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D006718:Homosteroids; D014404:Tubulin; C539406:nakiterpiosin; C547351:nakiterpiosinone; D004247:DNA