The Reactivity of Calicheamicin γ₁^I in the Minor Groove of DNA: The Decisive Role of the Environment

Abstract

Triggering and Bergman cyclization of calicheamicin gamma(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 gamma(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.

Structural and conformational features relevant to the anti‐tumor activity of calicheamicin γ

“…30 They used density functional theory (DFT) and molecular mechanics (MM) to describe the binding of the intact drug and cyclization intermediates of the drug in the DNA minor groove. Just recently, however, Kraka et al published results of their quantum chemical findings on the effect of environment on the reactivity of calicheamicin in the minor groove and the conformational properties of the transient biradical intermediate necessary for optimal cyclization and hydrogen abstraction.…”

Dieter Cremer's contribution to the field of theoretical chemistry

“…Dieter Cremer introduced the total and on‐top pair density as an appropriate test tool, in line with the interpretation given by Perdew, Savin, and Burke . This work paved the way for the future enediyne research in the Cremer group and beyond and prompted Dieter Cremer to work out a general scheme for the description of open‐shell molecules and multireference systems with DFT.…”

Novel insights on the DNA interaction of calicheamicin γ1I

“…However, a key point, not fully elucidated yet, is whether the modulation of Cal affinity determined for different DNA sequences is actually shared by its carbohydrate domain. This question derives from the higher DNA binding affinity showed by Cal when compared with the saccharide domain: this evidence suggests that all Cal structural domains actively contribute to the binding process …”

“…It is worth to remind that, from cleavage assay, the hydrophobic interaction between Cal and DNA was actually found to shift from an entropically to an enthalpically driven process upon temperature increments ( T ≥ 30°C) . Moreover, it is worth to underline that although NMR and computational studies support the potential formation of one ionic interaction between the nitrogen present on the aminosugar and the phosphate backbone, its contribution to the binding energetics is considered extremely reduced . Thus, no favorable entropic contribution connected to ion displacement from DNA spine should be expected.…”