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The Reactivity of Calicheamicin γ 1 I in the Minor Groove of DNA: The Decisive Role of the Environment
Author(s) -
Kraka Elfi,
Tuttle Tell,
Cremer Dieter
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700504
Subject(s) - calicheamicin , chemistry , crystallography , ab initio , ligand (biochemistry) , stereochemistry , density functional theory , hydrogen atom abstraction , hydrogen , computational chemistry , receptor , biochemistry , myeloid leukemia , organic chemistry , immunology , biology
Triggering and Bergman cyclization of calicheamicin γ 1 I outside and inside the minor groove of the duplex 9mer‐B‐DNA sequence d(CACTCCTGG) ⋅ d(CCAGGAGTG) were investigated by using density functional theory and molecular mechanics (DFT and MM) descriptions in which the ligand is completely described at the DFT and the receptor at the MM level. The calculated docking energy of calicheamicin γ 1 I (−12.5 kcal mol −1 ) is close to the measured value of −9.7 kcal mol −1 and the site specificity is in line with experimental observations. Calicheamicin is triggered in the minor groove in such a way that out of a cyclohexenone by Michael addition an E rather than a Z form of a cyclohexanone is formed, which in turn adopts a chair rather than a twistboat form. Decisive for the stereochemistry of the Michael addition is the orientation of the carbamate substituent at the headgroup of calicheamicin. Triggered calicheamicin can undergo the Bergman cyclization at body temperature only if present in its E chair form (activation enthalpy 16.4 kcal mol −1 ). An intermediate biradical is formed (docking energy −13.6 kcal mol −1 ), which has a sufficient lifetime to abstract two hydrogen atoms. Hydrogen abstraction is a two‐ rather than one‐step process and involves the C5(H5′) atom first and then the T22(H4′) atom in line with experimental observations. The decisive role of using a DFT rather than an MM description for the ligand is documented.