eprintid: 18236
rev_number: 16
userid: 1418
dir: disk0/00/01/82/36
datestamp: 2013-04-08 17:08:37
lastmod: 2019-02-02 16:56:35
status_changed: 2013-04-08 17:08:37
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Jung, WH
creators_name: Harrison, C
creators_name: Shin, Y
creators_name: Fournier, JH
creators_name: Balachandran, R
creators_name: Raccor, BS
creators_name: Sikorski, RP
creators_name: Vogt, A
creators_name: Curran, DP
creators_name: Day, BW
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creators_email: curran@pitt.edu
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creators_id: CURRAN
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title: Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
abstract: The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16- dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16- dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents. © 2007 American Chemical Society.
date: 2007-06-28
date_type: published
publication: Journal of Medicinal Chemistry
volume: 50
number: 13
pagerange: 2951 - 2966
refereed: TRUE
issn: 0022-2623
id_number: 10.1021/jm061385k
pmid: 17542572
mesh_headings: Animals
mesh_headings: Antineoplastic Agents--chemical synthesis
mesh_headings: Antineoplastic Agents--chemistry
mesh_headings: Antineoplastic Agents--pharmacology
mesh_headings: Binding, Competitive
mesh_headings: Cattle
mesh_headings: Cell Line, Tumor
mesh_headings: Drug Screening Assays, Antitumor
mesh_headings: Humans
mesh_headings: Macrolides--chemical synthesis
mesh_headings: Macrolides--chemistry
mesh_headings: Macrolides--pharmacology
mesh_headings: Microtubules--chemistry
mesh_headings: Stereoisomerism
mesh_headings: Structure-Activity Relationship
mesh_headings: Tubulin--chemistry
chemical_names: Antineoplastic Agents
chemical_names: Macrolides
chemical_names: Tubulin
chemical_names: dictyostatin
citation:   Jung, WH and Harrison, C and Shin, Y and Fournier, JH and Balachandran, R and Raccor, BS and Sikorski, RP and Vogt, A and Curran, DP and Day, BW  (2007) Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin.  Journal of Medicinal Chemistry, 50 (13).  2951 - 2966.  ISSN 0022-2623     
document_url: http://d-scholarship-dev.library.pitt.edu/18236/1/licence.txt