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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.JO

Abstract

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.

Authors+Show Affiliations

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.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16268636

Citation

Xiao, Xiangshu, and Mark Cushman. "Effect of E-ring Modifications in Camptothecin On Topoisomerase I Inhibition: a Quantum Mechanics Treatment." The Journal of Organic Chemistry, vol. 70, no. 23, 2005, pp. 9584-7.
Xiao X, Cushman M. Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: a quantum mechanics treatment. J Org Chem. 2005;70(23):9584-7.
Xiao, X., & Cushman, M. (2005). Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: a quantum mechanics treatment. The Journal of Organic Chemistry, 70(23), 9584-7.
Xiao X, Cushman M. 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. PubMed PMID: 16268636.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: a quantum mechanics treatment. AU - Xiao,Xiangshu, AU - Cushman,Mark, PY - 2005/11/5/pubmed PY - 2006/6/21/medline PY - 2005/11/5/entrez SP - 9584 EP - 7 JF - The Journal of organic chemistry JO - J Org Chem VL - 70 IS - 23 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 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. SN - 0022-3263 UR - https://www.unboundmedicine.com/medline/citation/16268636/Effect_of_E_ring_modifications_in_camptothecin_on_topoisomerase_I_inhibition:_a_quantum_mechanics_treatment_ L2 - https://doi.org/10.1021/jo0513360 DB - PRIME DP - Unbound Medicine ER -