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A structural relation to podophyllotoxin is the steganacin family. These were isolated from the extract of stems and stem bark of the east African tree Steganataenia araliacea in the early 1970s. In this series, steganicin 47 and stegananin 48 (Figure 17) are of similar potency, both being slightly weaker inhibitors of tubulin polymerization than podophyllotoxin (single-digit nanomolar). It appears that correct positioning of the trimethoxy ring is essential for activity. This is achieved through the eight-membered ring holding the biaryl moiety as the correct atropisomer. In this way inversion of the C-5 stereocenter or ring-opening results in an inactive molecule.138'139

In general, the SAR of this series (Figure 18) is dominated by the ability of the scaffold to position the trimethoxy aryl group correctly. For this reason, the stereochemistry about the C ring, be it a six- or eight-membered ring, is critical.

7.04.2.2.3 Combretastatins

The combretastatins 49 consist of a group of compounds isolated from the root bark or stem of the South African tree Combretum caffrum. The first molecules in this series were characterized in 1982 ( ). Since that time many related compounds have been discovered, of which combretastatin A-4 50, with single-digit nanomolar cytotoxicity in cell culture, is the most potent.141 Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized.

In the A ring, replacing the 4-methoxy with a phenol reduced activity significantly, although inhibition of tubulin polymerization is not affected. Increasing the size of the ether at this position destroys both cytotoxicity and tubulin polymerization inhibition. The 5-methoxy group appears to be critical for activity.142 The strict requirements for activity in this portion of the molecule mirror the A ring of colchicine.

In the B ring, removal of the 3-hydroxyl reduces activity, but the compounds maintain potency. However, moving this methoxy around the ring or replacing it with a halide-, alkyl-, or nitrogen-containing group lowers activity severely.143 Inversion of the methoxy and hydroxy groups as in isocombretastatin 51 (Figure 20) results in an inactive compound in a similar fashion to that seen in the colchicine series. Glycosylation of this position results in low or no

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