Current Management and New Leads in Small Cell Lung Cancer

Greco, F. Anthony; Hainsworth, John D.

doi:10.1007/978-2-8178-0918-2_6

Cited by 1 publication

(1 citation statement)

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“…Taxol ( 1 ) isolated from the bark of Taxus brevifolia in the late 1960s, and its semisynthetic congener, Taxotere ( 2 ), have become the drugs of choice for the treatment of ovarian and breast cancer . In attempts to understand the action of Taxol at its microtubule target, extensive SAR studies have been conducted.…”

Section: Introductionmentioning

confidence: 99%

The Oxetane Ring in Taxol

et al. 2000

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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.

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Section: Introductionmentioning

confidence: 99%