O O

MeO' y "OMe OMe

The introduction of a hydroxyl on the B ring at the C-5 position is found in several related natural products as well as semisynthetic analogs. In general this is well tolerated, with a range of alkyl ethers and esters actually increasing the activity of the molecule. Replacement of the A ring with two methoxy groups, as found in sikkimotoxin 41, results in a 10-fold loss in cytotoxicity.

A number of quinoline and dihydroquinoline derivatives of podophyllotoxin have been synthesized (Figure 15).133 The trends for these compounds are similar to those in the podophyllotoxin, with the corresponding quinoline 42 and analogs having weak cytotoxicity. The dihydroquinolines are significantly more potent. In this series a number of A-ring compounds have been synthesized. The indane and the six-membered dioxane 43 rings are very potent, while the dimethoxy derivative is weaker. These results suggest that the requirements in this sector of the molecule may be due more to steric requirements than electronic. In the E ring there is a 10-fold loss of activity on removal of the 3'-methoxy compared with the 4'-methoxy in podophyllotoxin.

Azatoxin 44 was designed as a topoisomerase II inhibitor through rational design-based modeling from preexisting inhibitors (Figure 16).134 In screening against the National Cancer Institute (NCI) 60-cell-line panel, it was observed that this molecule showed a similar profile to colchicine-site tubulin destabilizers. Indeed, at low concentrations this was found to be the prevailing mechanism of action.135 It has been shown that the tubulin binding can be engineered out by the introduction of bulky groups at the C-11 position, while the topoisomerase II activity is removed either by methylation of the 4'-position to form methylazatoxin 45136 or by appending an aromatic ring to the indole functionality to form benz[e]aztoxin 46.137

MeO y OMe OR

Figure 16 Structures of azatoxin and analogs.

MeO y OMe OH

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