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Total synthesis and evaluation of vinblastine analogues containing systematic deep-seated modifications in the vindoline subunit ring system: Core redesign

Academic Article
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Overview

related to degree

  • Duncan, Katharine, Ph.D. in Chemistry, Scripps Research 2008 - 2014
  • Kato, Daisuke, Ph.D. in Chemical Biology, Scripps Research 2005 - 2011

authors

  • Schleicher, K. D.
  • Sasaki, Y.
  • Tam, A.
  • Kato, Daisuke
  • Duncan, Katharine
  • Boger, Dale

publication date

  • January 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.

subject areas

  • Antineoplastic Agents, Phytogenic
  • Drug Evaluation, Preclinical
  • Vinblastine
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Identity

PubMed Central ID

  • PMC3554876

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm3014376

PubMed ID

  • 23252481
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Additional Document Info

start page

  • 483

end page

  • 495

volume

  • 56

issue

  • 2

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