The oxetane ring in taxol

Numerous structure-activity studies combining synthesis and bioassay have b een 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 bi ological activity. This proposition is examined by application of a Taxol-e pothilone 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 func tion: (1) rigidification of the tetracyclic Taxol core to provide an approp riate framework for presenting the C-2, C-4, C-13 side chains to the microt ubule protein and (2) service as a hydrogen-bond acceptor. An energy decomp osition analysis for a series of Taxol analogues demonstrates that the oxet ane ring clearly operates by both mechanisms. However, a broader analysis o f four-membered ring containing compounds, C- and D-seco derivatives, and s tructures with no oxetane equivalent underscores that the four-membered rin g is not necessary for Taxol analogue bioactivity. Other functional groups and ligand-protein binding characteristics are fully capable or delivering Taxol biobehavior as effectively as the oxetane D-ring. This insight may co ntribute to the design and development of novel anticancer drugs.