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

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

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

Mark S Tichenor,John D Trzupek,David B Kastrinsky,Futoshi Shiga,Inkyu Hwang,Dale L Boger,

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.

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

MS Tichenor,JD Trzupek,DB Kastrinsky,F Shiga,I Hwang,DL Boger,

For similar environment and public health: environment: environment, controlled: temperature research abstracts see: environment and public health: environment: environment, controlled: temperature research

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 128

Page Numbers: 15683-96

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 13

MONTH: Dec

YEAR: 2006

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

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LANGUAGE: eng

NlmUniqueID: 7503056

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

KEYWORDS: Temperature

MESH TERMS: chemistry

Chemical & Substance for Abstract: Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer. Information

Substance Name: DNA

Registry Number: 9007-49-2

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

AFFILIATION: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA42056

ACRONYM: CA

MEDLINETA: J Am Chem Soc

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