R Spongistatins

The spongistatins are macrocyclic polyethers of marine origin (Figure 6).55 Spongistatin 1 12, the most highly studied member of this class of compounds, shows potent cytotoxicity against a range of tumor cell types with IC50 values in the low picomolar range. Its antiproliferative activity results from its interaction with microtubules by binding within the vinca domain but not at the vinca binding site.56 Initially, spongistatin 1 was thought to inhibit microtubule assembly, but more recently, an unusual mechanism involving microtubule severing, not simply altering the microtubule dynamics, was proposed.57 This compound has not advanced beyond the early preclinical stage due to a scarcity of material. The potency and scarcity of these compounds have made them highly attractive targets for total chemical synthesis. Several elegant strategies to this class of compounds have appeared in the scientific literature.58-64 Not only does this synthetic work have the potential to address the supply problem, but it also provides the opportunity for the expansion of the spongistatin SAR outside the scope of naturally occurring analogs. Pironetin

Pironetin 21, an unsaturated lactone originally isolated from a Streptomyces sp. fermentation broth, possesses both plant growth-regulatory and immunosuppressant activities.65-67 In addition, pironetin and structurally related analogs inhibit microtubule assembly by binding to tubulin near the vinca site (Figure 7). Replacement of the olefin with an epoxide,

Figure 7 Structures of pironetins.

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