Synthesis of 13C, 15N‐enriched α‐dicarbonyl model adducts to determine the utility of 13c and 15N NMR for studying mechanism‐based inactivation of cytochromes P‐450 by substituted dichloroacetamides

Scott J. Weiner, Susan M. Holl, Douglas F. Covey

Research output: Contribution to journalArticlepeer-review

Abstract

To determine the feasibility of using NMR to study the inactivation of cytochromes P‐450 by dichloroacetamide‐containing mechanism‐based inactivators, 13C, 15N‐enriched compounds were synthesized, modeling adducts between the nucleophilic side‐chains of cysteine, lysine, serine (threonine) and tyrosine and the α‐aminooxoacyl chloride that presumably results from enzymatic conversion of a dichloroacetamide‐containing inhibitor. 13C chemical shifts of the carbonyls attached to the nucleophiles easily distinguish the model cysteine adduct (δ 192.3) from the other adducts (δ 159.6–161.8). Although the other adducts cannot be distinguished at this carbon, the carbonyl attached to the 15N two bonds away can distinguish the lysine mimic (δ 161.2 or 161.3) from the serine (threonine) and tyrosine mimics (δ 156.1–158.1). These assignments were made by comparing 15N/13C J values and were confirmed by solid‐state rotational echo double resonance (REDOR) studies. Finally, aminooxo‐15N chemical shifts three bonds removed from the nucleophile can distinguish adducts formed to lysine (δ 108.3), cysteine (δ 104.8) and oxygen‐containing side‐chains (δ 112.8–113.9).

Original languageEnglish
Pages (from-to)122-127
Number of pages6
JournalMagnetic Resonance in Chemistry
Volume32
Issue number2
DOIs
StatePublished - Feb 1994

Keywords

  • C
  • Mechanism‐based inactivator
  • N
  • NMR
  • P‐450
  • REDOR
  • Suicide substrate
  • α‐Diketo adducts

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