Etherification DIMINISHES activity I

Figure 3 Maytansine SAR.

Limited side-chain alterations TOLERATED

OMe Rhizoxin (8) t

Figure 4 Rhizoxin SAR.

endosymbiotic bacterium from the genus Burkholderia.38 The absolute structure of rhizoxin, unknown at the time of its discovery, was determined in 1986 by single-crystal x-ray crystallographic analysis.39 Rhizoxin was found to inhibit tubulin polymerization and to destabilize microtubules by rapid, reversible tubulin binding within the vinca domain at the maytansine binding site.40 Several semisynthetic analogs of rhizoxin have been prepared, and the resulting SAR data are detailed in Figure 4.41'42 In addition, a number of total chemical syntheses of rhizoxin have been reported. The chemistry and biology of this compound have recently been reviewed.43

Rhizoxin has been advanced through preclinical and clinical evaluation to phase II. Preclinically, xenograft models showed a strong schedule dependence with antitumor activity evident only with prolonged exposure. In human evaluation of this compound, a 5-min bolus injection showed only modest antitumor activity, possibly due to rapid systemic clearance. To address this pharmacokinetic issue and to exploit the potential for schedule-dependent behavior of rhizoxin, a dose and infusion time-escalating study was initiated. This study reached a dose of 1.2 mgm _ 2 infused over 72 h every 3 weeks. Dose-limiting toxicities were mucositis and neutropenia. No antitumor activity was observed.44 Halichondrins

The halichondrins are polyether macrolides isolated from a variety of marine sponges.45-49 Halichondrin B 9 (Figure 5), the most potent member of this family, is a noncompetitive inhibitor of vinblastine binding to tubulin and likely inhibits microtubule formation through binding at a unique site within the vinca domain.50,51 Analysis of the halichondrin SAR revealed that significant structural variations of the C-30 to C-54 side chain have only minimal effects on potency.

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