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November 12, 2008Journal of the American Chemical SocietyOpen Access

An Additional Spirocyclization for Duocarmycin SA

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Authors

KMKaren S. MacMillanThe University of Texas Southwestern Medical CenterDBDale L. BogerUniversity of East Anglia

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Implication

Biochemical analysis reveals an alternative indole-mediated spirocyclization pathway for duocarmycin SA activation, highlighting noncanonical DNA alkylation mechanisms in antitumor agents.

Key Points

  • To identify and characterize an alternative activation pathway for the duocarmycin SA alkylation subunit involving indole NH deprotonation and cyclopropane formation.
  • Synthesized and structurally characterized an alternative spirocyclization product generated via indole NH deprotonation.
  • Assessed relative chemical reactivity, intrinsic reaction regioselectivity, and biological cytotoxicity.
  • Measured DNA alkylation selectivity, reaction rates, and overall efficiency, including isolating and quantifying the adenine N3 adduct.
  • Demonstrated an effective alternative to para-spirocyclization that successfully forms an active cyclopropane-containing subunit.
  • Confirmed targeted DNA alkylation through successful isolation, characterization, and quantitation of the resulting adenine N3 adduct.
  • Defined the distinctive intrinsic regioselectivity and reactivity profiles associated with the alternative spirocyclization pathway.

Cite This Study

MacMillan et al. (2008) studied this question.

synapsesocial.com/papers/6a7ddbedfcc540eda03c9485https://doi.org/10.1021/ja806593w
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Also Consider

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  1. 1(+)- and ent-(-)-Duocarmycin SA and (+)- and ent-(-)-N-BOC-DSA DNA Alkylation Properties.Alkylation Site Models That Accommodate the Offset AT-Rich Adenine N3 Alkylation Selectivity of the Enantiomeric Agents1994 · 118 citations
  2. 2Molecular basis for sequence-specific DNA alkylation by CC-10651988 · 145 citations
  3. 3Synthesis and evaluation of aborted and extended CC-1065 functional analogs: (+)- and (-)-CPI-PDE-I1, (+)- and (-)-CPI-CDPI1, and (.+-.)-, (+)-, and (-)-CPI-CDPI3. Preparation of key partial structures and definition of an additional functional role of the CC-1065 central and right-hand subunits1990 · 78 citations
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