Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

  • Tichenor, Mark, Ph.D. in Chemistry, Scripps Research 2002 - 2007
  • Trzupek, John, Ph.D. in Chemistry, Scripps Research 2001 - 2006
  • Kastrinsky, David, Ph.D. in Synthetic Organic Chemistry, Scripps Research 2000 - 2005

authors

  • Tichenor, Mark
  • Trzupek, John
  • Kastrinsky, David
  • Shiga, F.
  • Hwang, I.
  • Boger, Dale

publication date

  • December 2006

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5'-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.

subject areas

  • Adenine
  • Alkylating Agents
  • Alkylation
  • Antibiotics, Antineoplastic
  • Base Pairing
  • Base Sequence
  • DNA
  • Hydrogen-Ion Concentration
  • Indoles
  • Kinetics
  • Models, Chemical
  • Pyrroles
  • Stereoisomerism
  • Streptomyces
  • Temperature
scroll to property group menus

Identity

PubMed Central ID

  • PMC2515590

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja064228j

PubMed ID

  • 17147378
scroll to property group menus

Additional Document Info

start page

  • 15683

end page

  • 15696

volume

  • 128

issue

  • 49

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support