Abstract
Triggering and Bergman cyclization of calicheamicin γ 1I 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 y1I (-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.
| Language | English |
|---|---|
| Pages | 9256-9269 |
| Number of pages | 14 |
| Journal | Chemistry - A European Journal |
| Volume | 13 |
| Issue number | 33 |
| Early online date | 8 Nov 2007 |
| DOIs | |
| Publication status | Published - 16 Nov 2007 |
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Keywords
- ab initio calculations
- calicheamicin
- DNA damage
- environmental effects
- reaction mechanisms
Cite this
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The reactivity of calicheamicin γ1i in the minor groove of DNA : the decisive role of the environment. / Kraka, Elfi; Tuttle, Tell; Cremer, Dieter.
In: Chemistry - A European Journal , Vol. 13, No. 33, 16.11.2007, p. 9256-9269.Research output: Contribution to journal › Article
TY - JOUR
T1 - The reactivity of calicheamicin γ1i in the minor groove of DNA
T2 - Chemistry - A European Journal
AU - Kraka, Elfi
AU - Tuttle, Tell
AU - Cremer, Dieter
PY - 2007/11/16
Y1 - 2007/11/16
N2 - Triggering and Bergman cyclization of calicheamicin γ 1I 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 y1I (-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.
AB - Triggering and Bergman cyclization of calicheamicin γ 1I 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 y1I (-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.
KW - ab initio calculations
KW - calicheamicin
KW - DNA damage
KW - environmental effects
KW - reaction mechanisms
UR - http://www.scopus.com/inward/record.url?scp=36549030815&partnerID=8YFLogxK
UR - https://onlinelibrary.wiley.com/journal/15213765
U2 - 10.1002/chem.200700504
DO - 10.1002/chem.200700504
M3 - Article
VL - 13
SP - 9256
EP - 9269
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 33
ER -