The oxetane ring in taxol.
Numerous structure-activity studies combining synthesis and bioassay have been performed for the anti-cancer drug Taxol. The four-membered D-ring, an oxetane, is one of four structural features regarded to be essential for biological activity. This proposition is examined by application of a Taxol-epothilone minireceptor, K(i) estimation for microtubule binding and docking of Taxol analogues into a model of the Taxol-tubulin complex. In this way, we evaluate the two characteristics considered responsible for oxetane function: (1) rigidification of the tetracyclic Taxol core to provide an appropriate framework for presenting the C-2, C-4, C-13 side chains to the microtubule protein and (2) service as a hydrogen-bond acceptor. An energy decomposition analysis for a series of Taxol analogues demonstrates that the oxetane ring clearly operates by both mechanisms. However, a broader analysis of four-membered ring containing compounds, C- and D-seco derivatives, and structures with no oxetane equivalent underscores that the four-membered ring is not necessary for Taxol analogue bioactivity. Other functional groups and ligand-protein binding characteristics are fully capable of delivering Taxol biobehavior as effectively as the oxetane D-ring. This insight may contribute to the design and development of novel anticancer drugs.
Wang
M
M
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
Cornett
B
B
Nettles
J
J
Liotta
D C
DC
Snyder
J P
JP
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D004988:Ethers, Cyclic / Q000737:chemistry*; D006860:Hydrogen Bonding; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D018942:Macrolides; D014404:Tubulin; C005287:oxetane; D017239:Paclitaxel