TY - JOUR
T1 - Effect of E-ring modifications in camptothecin on topoisomerase I inhibition
T2 - A quantum mechanics treatment
AU - Xiao, Xiangshu
AU - Cushman, Mark
PY - 2005/11/11
Y1 - 2005/11/11
N2 - Camptothecins (CPTs) are the prototypical class of topoisomerase I (Top1) inhibitors with significant anticancer activities. Structure-activity relationship studies have demonstrated that inverting the stereochemistry at C-20 (R-CPT) or changing the E-ring lactone to a lactam (CPT-lactam) abolishes the Topi inhibitory activity. The explanations that have been advanced for these effects are that there is either a failure of hydrogen bond formation involving the C-20 hydroxyl group of R-CPT or a failure of E-ring opening of the lactam, which have been proposed to be required for Top1 inhibition. We demonstrate here that the preferred conformation for the CPTs has the 20-Et pseudoaxial, while the 20-OH is pseudoequatorial, and therefore, the 20-OH groups in all the three CPT analogues (S-CPT, R-CPT, and CPT-lactam) are able to hydrogen bond with Asp533. The loss of the Top1 inhibitory activity by the latter two CPT analogues is attributed to the decreased π-π stacking interaction energy with the neighboring base pairs compared to the natural S-CPT. The differences in π-π stacking interaction energies are derived from the differential electrostatics on the E-ring.
AB - Camptothecins (CPTs) are the prototypical class of topoisomerase I (Top1) inhibitors with significant anticancer activities. Structure-activity relationship studies have demonstrated that inverting the stereochemistry at C-20 (R-CPT) or changing the E-ring lactone to a lactam (CPT-lactam) abolishes the Topi inhibitory activity. The explanations that have been advanced for these effects are that there is either a failure of hydrogen bond formation involving the C-20 hydroxyl group of R-CPT or a failure of E-ring opening of the lactam, which have been proposed to be required for Top1 inhibition. We demonstrate here that the preferred conformation for the CPTs has the 20-Et pseudoaxial, while the 20-OH is pseudoequatorial, and therefore, the 20-OH groups in all the three CPT analogues (S-CPT, R-CPT, and CPT-lactam) are able to hydrogen bond with Asp533. The loss of the Top1 inhibitory activity by the latter two CPT analogues is attributed to the decreased π-π stacking interaction energy with the neighboring base pairs compared to the natural S-CPT. The differences in π-π stacking interaction energies are derived from the differential electrostatics on the E-ring.
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U2 - 10.1021/jo0513360
DO - 10.1021/jo0513360
M3 - Article
C2 - 16268636
AN - SCOPUS:27744466429
SN - 0022-3263
VL - 70
SP - 9584
EP - 9587
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 23
ER -