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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 25, Number 1
BKCSDE 25(1)
January 20, 2004 

A Theoretical Study on the N-Alkylation of a Pyrimidine with a Cyclopropa[c]inden-5-one; A Model Pharmacophore of Duocarmycins and CC-1065
Keepyung Nahm
Simulation, Pharmacophore, Cyclopropa[c]inden-5-one, Duocarmycins
The N-alkylation of 4-aminopyrimidine with a tetrahydro-3-aza-cyclopropa[c]inden-5-one, which is a model reaction of the pharmacophore of duocarmycins, was studied with a quantum chemical method. We consider two factors for the acceleration of the N-alkylation; distortion and protonation of the model pharmacophores. The distortion of the spirocyclopropyl moiety in the model spirocyclopropylcyclohexadienone could induce an intrinsic energy of 3-4 kcal/mol, but the protonation on the carbonyl oxygen of the model cyclohexadienone lowers the transition energy of the N-alkylation of 4-aminopyrimidine dramatically (~46 kcal/mol) and is considered to play a major role in the enzyme reaction. The distorted and protonated spirocyclohexadienone is exothermally relieved to a phenol with the heat of reaction of -37 kcal/mol. The protonation process is proposed to be the mode of action of duocarmycins in the DNA alkylation.
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