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Molecular Mechanism of Action

Although cantharidin was identified as the active constituent of Mylabris in the early 1800s, the first stereospecific synthesis was not reported until the 1950s (Stork 1999), and the understanding of the molecular mechanism un derlying its biological actions remained elusive for another 40 years. Then, in a key study it was observed that cantharidin binds with high affinity to a specific and saturable binding site in a cytosolic fraction produced from homogenized mouse liver (Graziano et al. 1997, 1998). Purification revealed that the high affinity cantharidin-binding site was protein phosphatase type 2A (Li and Casida 1992), and further characterization demonstrated that cantharidin acts as a strong inhibitor of PP1 and PP2A and a weaker inhibitor of PP2B (Honkanen 1993). Today we know that cantharidin also affects PP4 and PP5 (Hastie and Cohen 1998; Borthwick et al. 2001; Honkanen and Golden 2002).

Cantharidin is the simplest inhibitor of PP1 and PP2A identified to date, and several studies have addressed the structure-activity relationship of cantharidin by testing the inhibitory effects of derivatives against PP1, PP2A, and PP2B (Sodeoka et al. 1997; McCluskey et al. 2000a,b, 2001; Essers etal 2001). Details of specific modifications have been discussed in recent reviews (McCluskey and Sakoff 2001; Honkanen and Golden 2002; McCluskey et al. 2002b), so here the discussion will be brief. The consensus is that ring opening is needed for inhibitory activity, as attempts to modify the anhydride of cantharidin that prevent ring opening suppress (or eliminate) the inhibitory activity against PP1 and PP2A (McCluskey and Sakoff 2001; McCluskey et al. 2002b). Modification of the 7-O bridgehead is not tolerated, and bulky substitutions at C5, or even modest substitutions at the C1/C4 bridgeheads, suppress inhibitor activity against PP2A (McCluskey et al. 2002b). Unfortunately, to date modifications that substantially improve the potency or the specificity of cantharidin towards PP1/PP2A have not been reported. Nonetheless, modifications of the anhydride moiety on norcan-tharidins to produce cantharimides have been shown to produce compounds that retain inhibitory activity (McCluskey et al. 2001). This suggests that the synthesis of additional analogs of cantharidin that retain biological activity should be possible, and analogs displaying selectivity (although modest) for PP1 have been reported (McCluskey et al. 2002). The synthesis of fluorinated cantharidin analogs have also been reported (Essers etal 2001). Unfortunately, the effects of fluorination on inhibitory activity were not reported.

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