Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: a quantum mechanics treatment.
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 Top1 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 pi-pi stacking interaction energy with the neighboring base pairs compared to the natural S-CPT. The differences in pi-pi stacking interaction energies are derived from the differential electrostatics on the E-ring.
Xiao
Xiangshu
X
Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Cushman
Mark
M
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000737:chemistry* / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008968:Molecular Conformation; D009692:Nucleic Acid Heteroduplexes; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D009692:Nucleic Acid Heteroduplexes; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin