Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: a quantum mechanics treatment

J Org Chem. 2005 Nov 11;70(23):9584-7. doi: 10.1021/jo0513360.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / chemistry*
  • Camptothecin / pharmacology*
  • DNA Topoisomerases, Type I / metabolism*
  • Hydrogen Bonding
  • Hydrolysis
  • Molecular Conformation
  • Nucleic Acid Heteroduplexes
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors


  • Antineoplastic Agents, Phytogenic
  • Nucleic Acid Heteroduplexes
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I
  • Camptothecin